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Journal Cover Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0027-5107
   Published by Elsevier Homepage  [3032 journals]
  • Ongoing evolution of Pseudomonas aeruginosa PAO1 sublines complicates
           studies of DNA damage repair and tolerance
    • Authors: Julia Sidorenko; Tatjana Jatsenko; Maia Kivisaar
      Pages: 26 - 37
      Abstract: Publication date: Available online 16 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Julia Sidorenko, Tatjana Jatsenko, Maia Kivisaar
      Sublines of the major P. aeruginosa reference strain PAO1 are derivatives of the original PAO1 isolate, which are maintained in laboratories worldwide. These sublines display substantial genomic and phenotypic variation due to ongoing microevolution. Here, we examined four sublines, MPAO1, PAO1-L, PAO1-DSM and PAO1-UT, originated from different laboratories, and six DNA polymerase-deficient mutants from the P. aeruginosa MPAO1 transposon library for their employment in elucidation of DNA damage repair and tolerance mechanisms in P. aeruginosa. We found that PAO1 subline PAO1-UT carries a large deletion encompassing the DNA damage inducible imuA-imuB-imuC cassette (PA0669-PA0671), which is implied in mutagenesis in several species. Furthermore, the genetic changes leading to variation in the functionality of the MexEF-OprN efflux system contributed largely to the phenotypic discordance between P. aeruginosa PAO1 sublines. Specifically, we identified multiple mutations in the mexT gene, which encodes a transcriptional regulator of the mexEF-oprN genes, mutations in the mexF, and complete absence of these genes. Of the four tested sublines, MPAO1 was the only subline with the functional MexEF-OprN multidrug efflux system. Active efflux through MexEF-OprN rendered MPAO1 highly resistant to chloramphenicol and ciprofloxacin. Moreover, the functions of specialized DNA polymerase IV and nucleotide excision repair (NER) in 4-NQO-induced DNA damage tolerance appeared to be masked in MPAO1, while were easily detectable in other sublines. Finally, the frequencies of spontaneous and MMS-induced Rifr mutations were also significantly lower in MPAO1 in comparison to the PAO1 sublines with impaired MexEF-OprN efflux system. The MexEF-OprN-attributed differences were also observed between MPAO1 and MPAO1-derived transposon mutants from the two-allele transposon mutant collection. Thus, the accumulating mutations and discordant phenotypes of the PAO1 derivatives challenge the reproducibility and comparability of the results obtained with different PAO1 sublines and also limit the usage of the MPAO1 transposon library in DNA damage tolerance and mutagenesis studies.

      PubDate: 2017-03-21T06:13:29Z
      DOI: 10.1016/j.mrfmmm.2017.03.005
      Issue No: Vol. 797-799 (2017)
  • Cyto-genotoxic and DNA methylation changes induced by different crystal
           phases of TiO2-np in bronchial epithelial (16-HBE) cells
    • Authors: Manosij Ghosh; Deniz Öner; Radu-Corneliu Duca; Stevan M. Cokic; Sven Seys; Stef Kerkhofs; Kirsten Van Landuyt; Peter Hoet; Lode Godderis
      Pages: 1 - 12
      Abstract: Publication date: February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 796
      Author(s): Manosij Ghosh, Deniz Öner, Radu-Corneliu Duca, Stevan M. Cokic, Sven Seys, Stef Kerkhofs, Kirsten Van Landuyt, Peter Hoet, Lode Godderis
      With the increase in use of TiO2-np, a better understanding of their safety is important. In the present study the effect of different crystal phases of TiO2-np (anatase, rutile and anatase: rutile mixture; 20–26nm) were studied for cyto-genotoxicity and global DNA methylation and hydroxymethylation. Cytotoxic response was observed at a concentration of 25μg/ml for the particles tested. Results of comet and micronucleus (with and without CytB) assays revealed significant genotoxic effect of these particles. Flow cytometry revealed cell cycle arrest in the S-phase. Based on the results, toxicity of the particles could be correlated with their physico-chemical properties (i.e. smaller size and hydrodynamic diameter and larger surface area), anatase form being the most toxic. From the results of the cyto-genotoxicity assays, concentrations were determined for the epigenetic study. Effect on global DNA methylation and hydroxymethylation levels were studied at cyto-genotoxic (25μg/ml), genotoxic (12.5μg/ml) and sub cyto-genotoxic (3.25μg/ml) concentrations using LC–MS/MS analysis. Though no significant changes were observed for 3h treatment schedule; significant hypomethylation were observed at 24h for anatase (significant at 3.25 and 25μg/ml), rutile (significant at 3.25 and 25μg/ml) and anatase: rutile mixture (significant at 25μg/ml) forms. The results suggest that epigenetic changes could occur at sub cyto-genotoxic concentrations. And hence for complete characterization of nanoparticle toxicity, epigenetic studies should be performed along with conventional toxicity testing methods.

      PubDate: 2017-02-16T12:59:25Z
      DOI: 10.1016/j.mrfmmm.2017.01.003
      Issue No: Vol. 796 (2017)
  • A Novel Type of Gene Interaction in D. melanogaster
    • Authors: B.F. Chadov; E.V. Chadova; N.B. Fedorova
      Pages: 27 - 30
      Abstract: Publication date: Available online 11 January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): B.F. Chadov, E.V. Chadova, N.B. Fedorova
      The genes interact according to classical mechanisms, namely, complementation, modification, polymery, and epistasis, in the cells and organisms carrying these genes. Here we describe a novel type of gene interaction when the interacting genes reside in parents, whereas the interaction event takes place in their progenies lacking these genes. The conditional mutations in the D. melanogaster male X chromosome caused the “prohibition on producing daughters” in its offspring. The chromosomal rearrangements in chromosomes 2 and 3 of its female partner removed the prohibition. The phenomena of “prohibition” and “removal of prohibition” appeared as a parental effect in both the male and female. Both phenomena ensued from the presence of the studied mutations in parents rather than their unviable or survived progenies. Thus, the gene interaction when the genes themselves are absent at the site of interaction and during the interaction event takes place in drosophila.

      PubDate: 2017-01-15T19:04:37Z
      DOI: 10.1016/j.mrfmmm.2017.01.002
      Issue No: Vol. 795 (2017)
  • Torsional stress promotes trinucleotidic expansion in spermatids
    • Authors: Olivier Simard; Seyedeh Raheleh Niavarani; Virginie Gaudreault; Guylain Boissonneault
      Abstract: Publication date: Available online 9 April 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Olivier Simard, Seyedeh Raheleh Niavarani, Virginie Gaudreault, Guylain Boissonneault
      Trinucleotide repeats are involved in various neurodegenerative diseases and are highly unstable both in dividing or non-dividing cells. In Huntington disease (HD), the age of onset of symptoms is inversely correlated to the number of CAG repeats within exon 1 of the HTT gene. HD shows paternal anticipation as CAG repeats are increased during spermatogenesis. CAG expansion were indeed found to be generated during the chromatin remodeling in spermatids where most histones are evicted and replaced by protamines. This process involves striking change in DNA topology since free supercoils must be eliminated. Using an in vitro CAG repeat reporter assay and a highly active nuclear extracts from spermatids, we demonstrate that free negative supercoils result in CAG TNR expansion at a stabilized hairpin. We also suggest a possible role for protamines in promoting localized torsional stress and consequently TNR expansion. The transient increase in torsional stress during spermiogenesis may therefore provide an ideal context for the generation of such secondary DNA structures leading to the paternal anticipation of trinucleotidic diseases.

      PubDate: 2017-04-11T07:40:12Z
      DOI: 10.1016/j.mrfmmm.2017.04.001
  • Towards precision prevention: Technologies for identifying healthy
           individuals with high risk of disease
    • Authors: Zachary D. Nagel; Bevin P. Engelward; David J. Brenner; Thomas J. Begley; Robert W. Sobol; Jason H. Bielas; Peter J. Stambrook; Qingyi Wei; Jennifer J. Hu; Mary Beth Terry; Caroline Dilworth; Kimberly A. McAllister; Les Reinlib; Leroy Worth; Daniel T. Shaughnessy
      Abstract: Publication date: Available online 6 April 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Zachary D. Nagel, Bevin P. Engelward, David J. Brenner, Thomas J. Begley, Robert W. Sobol, Jason H. Bielas, Peter J. Stambrook, Qingyi Wei, Jennifer J. Hu, Mary Beth Terry, Caroline Dilworth, Kimberly A. McAllister, Les Reinlib, Leroy Worth, Daniel T. Shaughnessy
      The rise of advanced technologies for characterizing human populations at the molecular level, from sequence to function, is shifting disease prevention paradigms toward personalized strategies. Because minimization of adverse outcomes is a key driver for treatment decisions for diseased populations, developing personalized therapy strategies represents an important dimension of both precision medicine and personalized prevention. In this commentary, we highlight recently developed enabling technologies in the field of DNA damage, DNA repair, and mutagenesis. We propose that omics approaches and functional assays can be integrated into population studies that fuse basic, translational and clinical research with commercial expertise in order to accelerate personalized prevention and treatment of cancer and other diseases linked to aberrant responses to DNA damage. This collaborative approach is generally applicable to efforts to develop data-driven, individualized prevention and treatment strategies for other diseases. We also recommend strategies for maximizing the use of biological samples for epidemiological studies, and for applying emerging technologies to clinical applications.
      Graphical abstract image

      PubDate: 2017-04-11T07:40:12Z
      DOI: 10.1016/j.mrfmmm.2017.03.007
  • Biotesting of water of Lake Sevan with Tradescantia (clone 02)
    • Authors: R.E. Avalyan; E.A. Aghajanyan; A. Khosrovyan; A.L. Atoyants; A.E. Simonyan; R.M. Aroutiounian
      Abstract: Publication date: Available online 31 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): R.E. Avalyan, E.A. Aghajanyan, A. Khosrovyan, A.L. Atoyants, A.E. Simonyan, R.M. Aroutiounian
      For many decades water resources in Armenia have been affected by anthropogenic activity, consequently, a regular bioindication of genotoxic effects of the water bodies is desirable. The genotoxicity of water samples collected from different parts of Lake Sevan were assessed by means of Trad-SHM (stamen hair mutation) assay using Tradescantia (clone 02). Here we report a significant increase in the frequency of somatic mutations and morphological changes in the Tradescantia inflorescences exposed to the water samples compared to the control. The somatic mutations (recessive mutation and white mutation events) were mostly linked to the concentration of Al, Ni, As, Co and Pb in Artanish, Tsapatakh and Karchaghbyur, Noradus, Martuni and Litchk, while morphological changes (non-surviving hairs) were related to Co level in Tsapatakh and Karchaghbyur. The results obtained show that Lake Sevan contains substances which may cause genotoxicity and teratogenicity in Tradescantia and probably also in aquatic animals. The results also show that Trad-SHM assay can be used for monitoring natural resources.

      PubDate: 2017-04-04T07:07:06Z
      DOI: 10.1016/j.mrfmmm.2017.03.006
  • The Legacy of William Morgan: The PNNL Years
    • Authors: Antone L. Brooks
      Abstract: Publication date: Available online 18 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Antone L. Brooks

      PubDate: 2017-03-21T06:13:29Z
      DOI: 10.1016/j.mrfmmm.2017.03.002
  • Transmission of persistent ionizing radiation-induced foci through cell
           division in human primary cells
    • Authors: Aurelie Vaurijoux; Pascale Voisin; Amelie Freneau; Joan Francesc Barquinero; Gaetan Gruel
      Abstract: Publication date: Available online 10 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Aurelie Vaurijoux, Pascale Voisin, Amelie Freneau, Joan Francesc Barquinero, Gaetan Gruel
      Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (γH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24hours after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5Gy had at least one of these persistent IRIF 24hours after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells.

      PubDate: 2017-03-16T06:00:01Z
      DOI: 10.1016/j.mrfmmm.2017.03.003
           AND HOW
    • Authors: R. Julian Preston
      Abstract: Publication date: Available online 8 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): R. Julian Preston
      The process of setting radiation protection standards requires the interaction of a number of international and national organizations that in turn require the input of scientific and regulatory experts. Bill Morgan served in an expert capacity for several of these organizations particularly for the application of radiation biology data to risk assessment. He brought great enthusiasm and dedication to these committee efforts. In fact, he really enjoyed this type of service. The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), for example, provides comprehensive reviews of the input data for radiation risk assessments. In this context, they do not conduct risk assessments. In Europe, a research component of the risk assessment process is provided by the Multidisciplinary European Low Dose Initiative (MELODI). Specific issue areas are identified for which additional research can aid in reducing uncertainty in risk assessments. The International Commission for Radiological Protection (ICRP) uses these types of input data to develop nominal cancer risk estimates as input data for establishing dose limits for the public and workers. A similar regulatory role is provided in the US by the National Council on Radiation Protection and Measurements (NCRP). The NCRP Reports address the underlying principles for setting regulatory dose limits for the US public and workers; these differ to a limited extent from those of ICRP. The implementation of dose limits is conducted by individual countries but with significant guidance by the International Atomic Energy Agency (IAEA) through its Basic Safety Standards. The role of other national and international organizations are discussed in this same framework.

      PubDate: 2017-03-09T11:12:14Z
      DOI: 10.1016/j.mrfmmm.2017.03.004
  • Mitochondrial DNA damage and oxidative damage in HL-60 cells exposed to
           900MHz radiofrequency fields
    • Authors: Yulong Sun; Lin Zong; Zhen Gao; Shunxing Zhu; Jian Tong; Yi Cao
      Abstract: Publication date: Available online 7 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yulong Sun, Lin Zong, Zhen Gao, Shunxing Zhu, Jian Tong, Yi Cao
      HL-60 cells, derived from human promyelocytic leukemia, were exposed to continuous wave 900MHz radiofrequency fields (RF) at 120μW/cm2 power intensity for 4hours/day for 5 consecutive days to examine whether such exposure is capable damaging the mitochondrial DNA (mtDNA) mediated through the production of reactive oxygen species (ROS). In addition, the effect of RF exposure was examined on 8-hydroxy-2’-dexoyguanosine (8-OHdG) which is a biomarker for oxidative damage and on the mitochondrial synthesis of adenosine triphosphate (ATP) which is the energy required for cellular functions. The results indicated a significant increase in ROS and significant decreases in mitochondrial transcription factor A, mtDNA polymerase gamma, mtDNA transcripts and mtDNA copy number in RF-exposed cells compared with those in sham-exposed control cells. In addition, there was a significant increase in 8-OHdG and a significant decrease in ATP in RF-exposed cells. The response in positive control cells exposed to gamma radiation (GR, which is also known to induce ROS) was similar to those in RF-exposed cells. Thus, the overall data indicated that RF exposure was capable of inducing mtDNA damage mediated through ROS pathway which also induced oxidative damage. Prior-treatment of RF- and GR-exposed the cells with melatonin, a well-known free radical scavenger, reversed the effects observed in RF-exposed cells.

      PubDate: 2017-03-09T11:12:14Z
      DOI: 10.1016/j.mrfmmm.2017.03.001
    • Abstract: Publication date: February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 796

      PubDate: 2017-03-09T11:12:14Z
  • Targeted Cytoplasmic Irradiation and Autophagy
    • Authors: Jinhua Wu; Bo Zhang; Yen-Ruh Wuu; Mercy M. Davidson; Tom K. Hei
      Abstract: Publication date: Available online 1 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jinhua Wu, Bo Zhang, Yen-Ruh Wuu, Mercy M. Davidson, Tom K. Hei
      The effect of ionizing irradiation on cytoplasmic organelles is often underestimated because the general dogma considers direct DNA damage in the nuclei to be the primary cause of radiation induced toxicity. Using a precision microbeam irradiator, we examined the changes in mitochondrial dynamics and functions triggered by targeted cytoplasmic irradiation with α-particles. Mitochondrial dysfunction induced by targeted cytoplasmic irradiation led to activation of autophagy, which degraded dysfunctional mitochondria in order to maintain cellular energy homeostasis. The activation of autophagy was cytoplasmic irradiation-specific and was not detected in nuclear irradiated cells. This autophagic process was oxyradical-dependent and required the activity of the mitochondrial fission protein dynamin related protein 1 (DRP1). The resultant mitochondrial fission induced phosphorylation of AMP activated protein kinase (AMPK) which leads to further activation of the extracellular signal-related kinase (ERK) 1/2 with concomitant inhibition of the mammalian target of rapamycin (mTOR) to initiate autophagy. Inhibition of autophagy resulted in delayed DNA damage repair and decreased cell viability, which supports the cytoprotective function of autophagy. Our results reveal a novel mechanism in which dysfunctional mitochondria are degraded by autophagy in an attempt to protect cells from toxic effects of targeted cytoplasmic radiation.

      PubDate: 2017-03-03T14:04:54Z
      DOI: 10.1016/j.mrfmmm.2017.02.004
  • Analysis of Microsatellite Instability in CRISPR/Cas9 Editing Mice
    • Authors: Xueyun Huo; Yating Du; Jing Lu; Meng Guo; Zhenkun Li; Shuangyue Zhang; Xiaohong Li; Zhenwen Chen; Xiaoyan Du
      Abstract: Publication date: Available online 28 February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Xueyun Huo, Yating Du, Jing Lu, Meng Guo, Zhenkun Li, Shuangyue Zhang, Xiaohong Li, Zhenwen Chen, Xiaoyan Du
      Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR- associated (Cas) protein 9 system is a novel and powerful tool which is widely used for genome editing. CRISPR/Cas9 is RNA-guided and can lead to desired genomic modifications. However, whether the CRISPR/Cas9-mediated genome editing causes genomic alterations and genomic instability, such as microsatellite instability (MSI), is still unknown. Here we detected MSI in 21 CRISPR/Cas9 mouse strains using a panel of 42 microsatellite loci which were selected from our previous studies. Surprisingly, MSI occurrence was common in CRISPR/Cas9 modified genome, and most of the strains (19/21, 90.5%) examined showed MSI. Of 42 loci examined, 8 loci (8/42, 19.05%) exhibited MSI in the Cas9 editing mice. The Ttll9 (4/42, 9.5%) were the most unstable strains, and D10Mit3 and D10Mit198 (9/21, 42.9%) was considered to be the most “hot” locus in the Cas9 strains we tested. Through analyzing the mutation of microsatellite loci, we provide new insights into the genomic alterations of CRISPR/Cas9 models and it will help us for a better understanding of this powerful technology.

      PubDate: 2017-03-03T14:04:54Z
      DOI: 10.1016/j.mrfmmm.2017.02.003
  • Induction of the Long Noncoding RNA NBR2 from the Bidirectional BRCA1
           Promoter Under Hypoxic Conditions
    • Authors: J. Erin Wiedmeier; Anna Ohlrich; Adrian Chu; Michael R. Rountree; Mitchell S. Turker
      Abstract: Publication date: Available online 16 February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): J. Erin Wiedmeier, Anna Ohlrich, Adrian Chu, Michael R. Rountree, Mitchell S. Turker
      BRCA1 plays an important role in preventing breast cancer and is often silenced or repressed in sporadic cancer. The BRCA1 promoter is bidirectional: it drives transcription of the long non-coding (lnc) NBR2 transcript in the opposite orientation relative to the BRCA1 transcript. Hypoxic conditions repress BRCA1 transcription, but their effect on expression of the NBR2 transcript has not been reported. We used quantitative RT-PCR to measure BRCA1 and NBR2 transcript levels in 0% and 1% oxygen in MCF-7 breast cancer cells and found that NBR2 transcript levels increased as a function of time under hypoxic conditions, whereas BRCA1 mRNA levels were repressed. Hypoxic conditions were ineffective in reducing BRCA1 mRNA in UACC-3199 breast cancer cell line, which is reported to have an epigenetically silenced BRCA1 promoter, even though appreciable level of BRCA1 and NBR2 mRNA were detected. Significant recovery back to baseline RNA levels occurred within 48hours after the MCF-7 cells were restored to normoxic conditions. We used a construct with the 218bp minimal BRCA1 promoter linked to marker genes to show that this minimal promoter repressed expression bidirectionally under hypoxic conditions, which suggests that the elements necessary for induction of NBR2 are located elsewhere.

      PubDate: 2017-02-16T12:59:25Z
      DOI: 10.1016/j.mrfmmm.2017.02.001
  • Modulation of Modeled Microgravity on Radiation-Induced Adaptive Response
           of Root Growth in Arabidopsis thaliana
    • Authors: Chenguang Deng; Ting Wang; Jingjing Wu; Wei Xu; Huasheng Li; Min Liu; Lijun Wu; Jinying Lu; Po Bian
      Abstract: Publication date: Available online 14 February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Chenguang Deng, Ting Wang, Jingjing Wu, Wei Xu, Huasheng Li, Min Liu, Lijun Wu, Jinying Lu, Po Bian
      Space particles have an inevitable impact on organisms during space missions; radio-adaptive response (RAR) is a critical radiation effect due to both low-dose background and sudden high-dose radiation exposure during solar storms. Although it is relevant to consider RAR within the context of microgravity, another major space environmental factor, to our knowledge, there is no evidence yet as to its effects on RAR. In the present study, we established an experimental method for detecting the effects of gamma-irradiation on the primary root growth of Arabidopsis thaliana, in which RAR of root growth was significantly induced by several dose combinations. Microgravity was simulated using a two-dimensional rotation clinostat. It was shown that RAR of root growth was significantly inhibited under the modeled microgravity condition, and was absent in pgm-1 plants that had impaired gravity sensing in root tips. These results suggest that RAR could be modulated in microgravity. Time course analysis showed that microgravity affected either the development of radio-resistance induced by priming irradiation, or the responses of plants to challenging irradiation. Consistently, priming irradiation-induced expressions of DNA repair genes (AtKu70 and AtRAD54) were attenuated in microgravity, and reduced DNA repair efficiency in response to challenging irradiation was also observed after treatment with the modeled microgravity. In plant roots, the polar transportation of phytohormone auxin is regulated by gravity, and treatment with an exogenous auxin (indole-3-acetic acid) prevented the induction of RAR of root growth, suggesting that auxin might play a regulatory role in the interaction between microgravity and RAR of root growth.

      PubDate: 2017-02-16T12:59:25Z
      DOI: 10.1016/j.mrfmmm.2017.02.002
    • Abstract: Publication date: January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 795

      PubDate: 2017-02-05T12:26:23Z
  • The DNA damage response of C. elegans affected by gravity sensing and
           radiosensitivity during the Shenzhou-8 spaceflight
    • Authors: Ying Gao; Dan Xu; Lei Zhao; Yeqing Sun
      Abstract: Publication date: Available online 7 January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ying Gao, Dan Xu, Lei Zhao, Yeqing Sun
      Space radiation and microgravity are recognized as primary and inevitable risk factors for humans traveling in space, but the reports regarding their synergistic effects remain inconclusive and vary across studies due to differences in the environmental conditions and intrinsic biological sensitivity. Thus, we studied the synergistic effects on transcriptional changes in the global genome and DNA damage response (DDR) by using dys-1 mutant and ced-1 mutant of C. elegans, which respectively presented microgravity-insensitivity and radiosensitivity when exposure to spaceflight condition (SF) and space radiation (SR). The dys-1 mutation induced similar transcriptional changes under both conditions, including the transcriptional distribution and function of altered genes. The majority of alterations were related to metabolic shift under both conditions, including transmembrane transport, lipid metabolic processes and proteolysis. Under SF and SR conditions, 12/14 and 10/13 altered pathways, respectively, were both grouped in the metabolism category. Out of the 778 genes involved in DDR, except eya-1 and ceh-34, 28 altered genes in dys-1 mutant showed no predicted protein interactions, or anti-correlated miRNAs during spaceflight. The ced-1 mutation induced similar changes under SF and SR; however, these effects were stronger than those of the dys-1 mutant. The additional genes identified were related to phosphorous/phosphate metabolic processes and growth rather than, metabolism, especially for environmental information processing under SR. Although the DDR profiles were significantly changed under both conditions, the ced-1 mutation favored DNA repair under SF and apoptosis under SR. Notably, 37 miRNAs were predicted to be involved in the DDR. Our study indicates that, the dys-1 mutation reduced the transcriptional response to SF, and the ced-1 mutation increased the response to SR, when compared with the wild type C. elegans. Although some effects were due to radiosensitivity, microgravity, depending on the dystrophin, exerts predominant effects on transcription in C. elegans during short-duration spaceflight.

      PubDate: 2017-01-08T18:38:51Z
      DOI: 10.1016/j.mrfmmm.2017.01.001
  • Synergism of dam, MutH, and MutS in methylation-directed mismatch repair
           in Escherichia coli
    • Authors: Changkun Hu; Yunqi Zhao; Huiyun Sun; Yixin Yang
      Abstract: Publication date: Available online 6 January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Changkun Hu, Yunqi Zhao, Huiyun Sun, Yixin Yang
      DNA mismatch repair (MMR) is a critical mutation surveillance system for recognizing and repairing erroneous insertion, deletion, and disincorporation of base. Major components of mismatch repair system consist of MutH, MutL, and MutS. Dam methylates adenine to distinguish newly synthesized daughter strands from the parent strands. Employing a tyrosine-auxotrophic E. coli FX-11 strain, the mutation frequency can be determined by the number of tyrosine revertants and the cell viability of FX-11 with deficiencies in dam and mismatch repair proteins. This study showed that mutS defect produced a higher mutation frequency than mutH did. Interestingly, double defects in dam and mutS synergistically produced a dramatically higher spontaneous mutation frequency than the summation of mutation frequencies of FX-11 strains with individual deficiency of dam or mutS, suggesting that Dam may work with MutHL to partially accomplish the task of recognizing the mismatch sites to retain partial mismatch repair capacity.

      PubDate: 2017-01-08T18:38:51Z
      DOI: 10.1016/j.mrfmmm.2016.12.002
  • Screen for genes involved in radiation survival of Escherichia coli and
           construction of a reference database
    • Authors: Neil J. Sargentini; Nicholas P. Gularte; Deborah A. Hudman
      Pages: 1 - 14
      Abstract: Publication date: November–December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 793–794
      Author(s): Neil J. Sargentini, Nicholas P. Gularte, Deborah A. Hudman
      A set of 3907 single-gene knockout (Keio collection) strains of Escherichia coli K-12 was examined for strains with increased susceptibility to killing by X- or UV-radiation. After screening with a high-throughput resazurin-based assay and determining radiation survival with triplicate clonogenic assays, we identified 76 strains (and associated deleted genes) showing statistically-significant increased radiation sensitivity compared to a control strain. To determine gene novelty, we constructed a reference database comprised of genes found in nine similar studies including ours. This database contains 455 genes comprised of 103 common genes (found 2–7 times), and 352 uncommon genes (found once). Our 76 genes includes 43 common genes and 33 uncommon (potentially novel) genes, i.e., appY, atoS, betB, bglJ, clpP, cpxA, cysB, cysE, ddlA, dgkA, dppF, dusB, elfG, eutK, fadD, glnA, groL, guaB, intF, prpR, queA, rplY, seqA, sufC,yadG, yagJ, yahD, yahO, ybaK, ybfA, yfaL, yhjV, and yiaL. Of our 33 uncommon gene mutants, 4 (12%) were sensitive only to UV-radiation, 10 (30%) only to X-radiation, and 19 (58%) to both radiations. Our uncommon mutants vs. our common mutants showed more radiation specificity, i.e., 12% vs. 9% (sensitive only to UV-); 30% vs. 16% (X-) and 58% vs. 74% (both radiations). Considering just our radiation-sensitive mutants, the median UV-radiation survival (75Jm−2) for 23 uncommon mutants was 6.84E-3 compared to 1.85E-3 for 36 common mutants (P=0.025). Similarly, the average X-radiation survival for 29 uncommon mutants was 1.08E-2, compared to 6.19E-3 for 39 common mutants (P=0.010). Comparing gene functions using MultiFun terms, uncommon genes tended to show less involvement in DNA repair-relevant categories (information transfer and cell processes), but greater involvement in seven other categories. Our analysis of 455 genes suggests cell survival and DNA repair processes are more complex than previously understood, and may be compromised by deficiencies in other processes.

      PubDate: 2016-10-08T07:03:07Z
      DOI: 10.1016/j.mrfmmm.2016.10.001
      Issue No: Vol. 793-794 (2016)
  • Mapping the factors affecting the frequency and types of micronuclei in an
           elderly population from Southern Bohemia
    • Authors: Andrea Rossnerova; Katerina Honkova; Jitka Pavlikova; Zuzana Freitinger Skalicka; Renata Havrankova; Ivo Solansky; Pavel Rossner; Radim J. Sram; Friedo Zölzer
      Pages: 32 - 40
      Abstract: Publication date: November–December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 793–794
      Author(s): Andrea Rossnerova, Katerina Honkova, Jitka Pavlikova, Zuzana Freitinger Skalicka, Renata Havrankova, Ivo Solansky, Pavel Rossner, Radim J. Sram, Friedo Zölzer
      The micronucleus assay is one of the most common methods used to assess chromosomal damage (losses or breaks) in human peripheral blood lymphocytes (PBL) in genetic toxicology. Most studies have focused on analyzing total micronuclei (MN), but identifying the content of MN can provide more detailed information. The main aim of this study was to map the factors affecting the frequency and types of micronuclei in binucleated cells (BNC) in elderly population. Fluorescence in situ hybridization using Human Pan Centromeric Chromosome Paint was used to identify centromere positive (CEN+) or centromere negative (CEN-) MN. A group of 95 men from Southern Bohemia, Czech Republic (average age 68.0±6.8 years) was followed repeatedly, in spring and fall 2014. The study participants were former workers of the uranium plant “MAPE Mydlovary” (processing uranium ore from 1962 to 1991), and controls. The general profile of individual types of MN, and the effect of the season, former uranium exposure, age, smoking status, weight, and X-ray examination on the level and type of MN were analyzed. The results of this study showed: (i) a stable profile of BNC with MN based on the number of MN during two seasons; (ii) an increase of the number of CEN+ MN from spring to fall; (iii) a lower frequency of the total MN in the exposed group than in controls with a significant difference in the percentage of aberrant cells (%AB.C.) in the fall; (iv) no clear effect of age, smoking and BMI on DNA damage in this group; (v) lower DNA damage levels in former uranium workers who received X-ray examination later in life. In summary, the results indicate a trend of seasonal changes of individual types of MN and suggest that former exposure can have a protective effect on the level of DNA damage in case of future exposure.

      PubDate: 2016-11-03T09:09:06Z
      DOI: 10.1016/j.mrfmmm.2016.10.004
      Issue No: Vol. 793-794 (2016)
  • Effects of Ru(CO)3Cl-glycinate on the developmental toxicities induced by
           X-ray and carbon-ion irradiation in zebrafish embryos
    • Authors: Rong Zhou; Jing’e Song; Jing Si; Hong Zhang; Bin Liu; Lu Gan; Xin Zhou; Yupei Wang; Junfang Yan; Qianjing Zhang
      Pages: 41 - 50
      Abstract: Publication date: November–December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 793–794
      Author(s): Rong Zhou, Jing’e Song, Jing Si, Hong Zhang, Bin Liu, Lu Gan, Xin Zhou, Yupei Wang, Junfang Yan, Qianjing Zhang
      The inhibitory effects of carbon monoxide (CO), generated by Ru(CO)3Cl-glycinate [CO-releasing molecule (CORM-3)], on developmental toxicity in zebrafish embryos induced by ionizing radiation with different linear energy transfer (LET) were studied. Zebrafish embryos at 5h post-fertilization were irradiated with X-ray (low-LET) and carbon-ion (high-LET) with or without pretreatment of CORM-3 1h before irradiation. CORM-3 pre-treatment showed a significant inhibitory effect on X-ray irradiation-induced developmental toxicity, but had little effect on carbon-ion irradiation-induced developmental toxicity. X-ray irradiation-induced significant increase in ROS levels and cell apoptosis could be modified by CORM-3 pretreatment. However, embryos exposed to carbon-ion irradiation showed significantly increase of cell apoptosis without obvious ROS generation, which could not be attenuated by CORM-3 pretreatment. CORM-3 could inhibit apoptosis induced by ionizing radiation with low-LET as an effective ROS scavenger. The expression of pro-apoptotic genes increased significantly after X-ray irradiation, but increased expression was reduced markedly when CORM-3 was applied before irradiation. Moreover, the protein levels of P53 and γ-H2AX increased markedly after X-ray irradiation, which could be modified by the presence of CORM-3. The protective effect of CORM-3 on X-ray irradiation occurred mainly by suppressing ROS generation and DNA damage, and thus inhibiting the activation of P53 and the mitochondrial apoptotic pathway, leading to the attenuation of cell apoptosis and consequently alleviating X-ray irradiation-induced developmental toxicity at lethal and sub-lethal levels.

      PubDate: 2016-11-10T11:15:49Z
      DOI: 10.1016/j.mrfmmm.2016.11.001
      Issue No: Vol. 793-794 (2016)
  • A pivotal role of the jasmonic acid signal pathway in mediating
           radiation-induced bystander effects in Arabidopsis thaliana
    • Authors: Ting Wang; Wei Xu; Chenguang Deng; Shaoxin Xu; Fanghua Li; Yuejin Wu; Lijun Wu; Po Bian
      Pages: 1 - 9
      Abstract: Publication date: September–October 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 791–792
      Author(s): Ting Wang, Wei Xu, Chenguang Deng, Shaoxin Xu, Fanghua Li, Yuejin Wu, Lijun Wu, Po Bian
      Although radiation-induced bystander effects (RIBE) in Arabidopsis thaliana have been well demonstrated in vivo, little is known about their underlying mechanisms, particularly with regard to the participating signaling molecules and signaling pathways. In higher plants, jasmonic acid (JA) and its bioactive derivatives are well accepted as systemic signal transducers that are produced in response to various environmental stresses. It is therefore speculated that the JA signal pathway might play a potential role in mediating radiation-induced bystander signaling of root-to-shoot. In the present study, pretreatment of seedlings with Salicylhydroxamic acid, an inhibitor of lipoxigenase (LOX) in JA biosynthesis, significantly suppressed RIBE-mediated expression of the AtRAD54 gene. After root irradiation, the aerial parts of A. thaliana mutants deficient in JA biosynthesis (aos) and signaling cascades (jar1-1) showed suppressed induction of the AtRAD54 and AtRAD51 genes and TSI and 180-bp repeats, which have been extensively used as endpoints of bystander genetic and epigenetic effects in plants. These results suggest an involvement of the JA signal pathway in the RIBE of plants. Using the root micro-grafting technique, the JA signal pathway was shown to participate in both the generation of bystander signals in irradiated root cells and radiation responses in the bystander aerial parts of plants. The over-accumulation of endogenous JA in mutant fatty acid oxygenation up-regulated 2 (fou2), in which mutation of the Two Pore Channel 1 (TPC1) gene up-regulates expression of the LOX and allene oxide synthase (AOS) genes, inhibited RIBE-mediated expression of the AtRAD54 gene, but up-regulated expression of the AtKU70 and AtLIG4 genes in the non-homologous end joining (NHEJ) pathway. Considering that NHEJ is employed by plants with increased DNA damage, the switch from HR to NHEJ suggests that over-accumulation of endogenous JA might enhance the radiosensitivity of plants in terms of RIBE.

      PubDate: 2016-08-04T15:57:56Z
      DOI: 10.1016/j.mrfmmm.2016.07.002
      Issue No: Vol. 791-792 (2016)
  • PCNA SUMOylation protects against PCNA polyubiquitination-mediated,
           Rad59-dependent, spontaneous, intrachromosomal gene conversion
    • Authors: Agnieszka Halas; Michal Krawczyk; Ewa Sledziewska-Gojska
      Pages: 10 - 18
      Abstract: Publication date: Available online 2 August 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Agnieszka Halas, Michal Krawczyk, Ewa Sledziewska-Gojska
      Homologous recombination is crucial in both the maintenance of genome stability and the generation of genetic diversity. Recently, multiple aspects of the recombination machinery functioning at arrested DNA replication forks have been established, yet the roles of diverse modifications of PCNA, the key platform organizing the replication complex, in intrachromosomal recombination have not been comprehensively elucidated. Here, we report how PCNA SUMOylation and/or polyubiquitination affects recombination between direct repeats in S. cerevisiae. Our results show that these PCNA modifications primarily affect gene conversion, whereas their effect on the recombination-mediated deletion of intervening sequence is much less obvious. Siz1-dependent PCNA SUMOylation strongly limits Rad52/Rad51/Rad59-dependent gene conversion. A 5- to 10-fold increase in the frequency of such recombination events is observed in Siz1-defective strains, but this increase is fully suppressed when PCNA polyubiquitination is also compromised. PCNA polyubiquitination can stimulate gene conversion in both PCNA SUMOylation-proficient and SUMOylation-deficient strains. On the other hand, in PCNA polyubiquitination-deficient strains, the lack of PCNA SUMOylation does not affect GC levels. Therefore, we postulate that the antirecombinogenic activity of Siz1 mainly concerns recombination induced by PCNA polyubiquitination. In the absence of PCNA SUMOylation, the frequency of PCNA polyubiquitination-mediated gene conversion is not only increased, but it is also channeled into the Rad59-dependent pathway. Additionally, we show a weak inhibitory effect of Rad5 on Rad52/Rad59-directed single-strand annealing.

      PubDate: 2016-08-04T15:57:56Z
      DOI: 10.1016/j.mrfmmm.2016.08.001
      Issue No: Vol. 791-792 (2016)
  • Influence of exposure to pesticides on telomere length in tobacco farmers:
           a biology system approach
    • Authors: Vivian Francília Silva Kahl; Juliana da Silva; Fernanda Rabaioli da Silva
      Pages: 19 - 26
      Abstract: Publication date: Available online 17 August 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Vivian Francília Silva Kahl, Juliana da Silva, Fernanda Rabaioli da Silva
      Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity.
      Graphical abstract image

      PubDate: 2016-08-18T16:53:57Z
      DOI: 10.1016/j.mrfmmm.2016.08.003
      Issue No: Vol. 791-792 (2016)
  • Mining potential biomarkers associated with space flight in Caenorhabditis
           elegans experienced Shenzhou-8 mission with multiple feature selection
    • Authors: Lei Zhao; Ying Gao; Dong Mi; Yeqing Sun
      Pages: 27 - 34
      Abstract: Publication date: Available online 17 August 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Lei Zhao, Ying Gao, Dong Mi, Yeqing Sun
      To identify the potential biomarkers associated with space flight, a combined algorithm, which integrates the feature selection techniques, was used to deal with the microarray datasets of Caenorhabditis elegans obtained in the Shenzhou-8 mission. Compared with the ground control treatment, a total of 86 differentially expressed (DE) genes in responses to space synthetic environment or space radiation environment were identified by two filter methods. And then the top 30 ranking genes were selected by the random forest algorithm. Gene Ontology annotation and functional enrichment analyses showed that these genes were mainly associated with metabolism process. Furthermore, clustering analysis showed that 17 genes among these are positive, including 9 for space synthetic environment and 8 for space radiation environment only. These genes could be used as the biomarkers to reflect the space environment stresses. In addition, we also found that microgravity is the main stress factor to change the expression patterns of biomarkers for the short-duration spaceflight.

      PubDate: 2016-08-18T16:53:57Z
      DOI: 10.1016/j.mrfmmm.2016.08.002
      Issue No: Vol. 791-792 (2016)
  • The role of DNA polymerase ζ in translesion synthesis across bulky DNA
           adducts and cross-links in human cells
    • Authors: Tetsuya Suzuki; Petr Grúz; Masamitsu Honma; Noritaka Adachi; Takehiko Nohmi
      Pages: 35 - 41
      Abstract: Publication date: Available online 25 August 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Tetsuya Suzuki, Petr Grúz, Masamitsu Honma, Noritaka Adachi, Takehiko Nohmi
      Translesion DNA synthesis (TLS) is a cellular defense mechanisms against genotoxins. Defects or mutations in specialized DNA polymerases (Pols) involved in TLS are believed to result in hypersensitivity to various genotoxic stresses. Here, DNA polymerase ζ (Pol ζ)-deficient (KO: knockout) and Pol ζ catalytically dead (CD) human cells were established and their sensitivity towards cytotoxic activities of various genotoxins was examined. The CD cells were engineered by altering the DNA sequence encoding two amino acids essential for the catalytic activity of Pol ζ, i.e., D2781 and D2783, to alanines. Both Pol ζ KO and CD cells displayed a prolonged cell cycle and higher incidence of micronuclei formation than the wild-type (WT) cells in the absence of exogenous genotoxic treatments, and the order of abnormality was CD>KO>WT cells. Both KO and CD cells exhibited higher sensitivity towards the killing effects of benzo[a]pyrene diol epoxide, mitomycin C, potassium bromate, N-methyl-N′-nitro-N-nitrosoguanidine, and ultraviolet C irradiation than WT cells, and there were no differences between the sensitivities of KO and CD cells. Interestingly, neither KO nor CD cells were sensitive to the cytotoxic effects of hydrogen peroxide. Since KO and CD cells displayed similar sensitivities to the genotoxins, we employed only KO cells to further examine their sensitivity to other genotoxic agents. KO cells were more sensitive to the cytotoxicity of 4-nitroquinoline N-oxide, styrene oxide, cisplatin, methyl methanesulfonate, and ethyl methanesulfonate than WT cells. However, the KO cells displayed sensitivity camptothecin, etoposide, bleomycin, hydroxyurea, crotonealdehyde, and methylglyoxal in a manner similar to the WT cells. Our results suggest that Pol ζ plays an important role in the protection of human cells by carrying out TLS across bulky DNA adducts and cross-links, but has no or limited role in the protection against strand-breaks in DNA.

      PubDate: 2016-08-27T17:30:13Z
      DOI: 10.1016/j.mrfmmm.2016.08.004
      Issue No: Vol. 791-792 (2016)
  • Occupational exposure to anesthetics leads to genomic instability,
           cytotoxicity and proliferative changes
    • Authors: Kátina M. Souza; Leandro G. Braz; Flávia R. Nogueira; Marajane B. Souza; Lahis F. Bincoleto; Aline G. Aun; José E. Corrente; Lídia R. Carvalho; José Reinaldo C. Braz; Mariana G. Braz
      Pages: 42 - 48
      Abstract: Publication date: Available online 9 September 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Kátina M. Souza, Leandro G. Braz, Flávia R. Nogueira, Marajane B. Souza, Lahis F. Bincoleto, Aline G. Aun, José E. Corrente, Lidia R. Carvalho, José Reinaldo C. Braz, Mariana G. Braz
      Data on the genotoxic and mutagenic effects of occupational exposure to the most frequently used volatile anesthetics are limited and controversial. The current study is the first to evaluate genomic instability, cell death and proliferative index in exfoliated buccal cells (EBC) from anesthesiologists. We also evaluated DNA damage and determined the concentrations of the anesthetic gases most commonly used in operating rooms. This study was conducted on physicians who were allocated into two groups: the exposed group, which consisted of anesthesiologists who had been exposed to waste anesthetic gases (isoflurane, sevoflurane, desflurane and nitrous oxide − N2O) for at least two years; and the control group, which consisted of non-exposed physicians matched for age, sex and lifestyle with the exposed group. Venous blood and EBC samples were collected from all participants. Basal DNA damage was evaluated in lymphocytes by the comet assay, whereas the buccal micronucleus (MN) cytome (BMCyt) assay was applied to evaluate genotoxic and cytotoxic effects. The concentrations of N2O and anesthetics were measured via a portable infrared spectrophotometer. The average concentration of waste gases was greater than 5 parts per million (ppm) for all of the halogenated anesthetics and was more than 170ppm for N2O, expressed as a time-weighted average. There was no significant difference between the groups in relation to lymphocyte DNA damage. The exposed group had higher frequencies of MN, karyorrhexis and pyknosis, and a lower frequency of basal cells compared with the control group. In conclusion, exposure to modern waste anesthetic gases did not induce systemic DNA damage, but it did result in genomic instability, cytotoxicity and proliferative changes, which were detected in the EBC of anesthesiologists. Thus, these professionals can be considered at risk for developing genetic alterations resulting from occupational exposure to these gases, suggesting the need to minimize this exposure.

      PubDate: 2016-09-15T19:30:03Z
      DOI: 10.1016/j.mrfmmm.2016.09.002
      Issue No: Vol. 791-792 (2016)
    • Authors: Inna B. Korzeneva; Svetlana V. Kostuyk; Elizaveta S. Ershova; Elena N. Skorodumova; Veronika F. Zhuravleva; Galina V. Pankratova; Irina V. Volkova; Elena V. Stepanova; Lev N. Porokhovnik; Natalia N. Veiko
      Pages: 49 - 60
      Abstract: Publication date: Available online 7 September 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Inna B. Korzeneva, Svetlana V. Kostuyk, Elizaveta S. Ershova, Elena N. Skorodumova, Veronika F. Zhuravleva, Galina V. Pankratova, Irina V. Volkova, Elena V. Stepanova, Lev N. Porokhovnik, Natalia N. Veiko
      A single exposure to ionizing radiation (IR) results in an elevated cell-free DNA (cfDNA) content in the blood plasma. In this case, the cfDNA concentration can be a marker of the cell death in the organism. However, a chronic exposure to a low-dose IR enhances both the endonuclease activity and titer of antibodies to DNA in blood plasma, resulting in a decrease of the total concentration of circulating cfDNA in exposed people. In this case, the total cfDNA concentration should not be considered as a marker of the cell death in an exposed body. We assumed that a pool of the cfDNA circulating in the exposed people contains DNA fragments, which are resistant to a double-strand break formation in the environment of the elevated plasma endonuclease activity, and can be accumulated in the blood plasma. In order to test this hypothesis, we studied the content of GC-rich sequences (69%GC) of the transcribed region of human ribosomal repeat (rDNA), as well as the content of AT-rich repeat (63%AT) of satellite III (1q12) in the cfDNA samples obtained from 285 individuals. We have found that a chronic exposure to gamma-neutron radiation (N=88) and tritium β-radiation (N=88) evokes an increase of the rDNA content (RrDNA index) and a decrease of the satellite III content (RsatIII index) in the circulating cfDNA as compared with the cfDNA of non-exposed people (N=109). Such index that simultaneously displays both the increase of rDNA content and decrease of satellite III content in the cfDNA (RrDNA/RsatIII) can be recommended as a marker of chronic processes in the body that involve the elevated cell death rate and/or increased blood plasma endonuclease activity.
      Graphical abstract image

      PubDate: 2016-09-10T18:49:48Z
      DOI: 10.1016/j.mrfmmm.2016.09.001
      Issue No: Vol. 791-792 (2016)
  • Abnormal mRNA Splicing but Normal Auditory Brainstem Response (ABR) in
           Mice with the Prestin (SLC26A5) IVS2-2A>G mutation
    • Authors: Jian Zhang; Ziyi Liu; Aoshuang Chang; Jie Fang; Yuqin Men; Yong Tian; Xiaomei Ouyang; Denise Yan; Aizhen Zhang; Xiaoyang Sun; Jie Tang; Xuezhong Liu; Jian Zuo; Jiangang Gao
      Pages: 1 - 7
      Abstract: Publication date: Available online 12 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jian Zhang, Ziyi Liu, Aoshuang Chang, Jie Fang, Yuqin Men, Yong Tian, Xiaomei Ouyang, Denise Yan, Aizhen Zhang, Xiaoyang Sun, Jie Tang, Xuezhong Liu, Jian Zuo, Jiangang Gao
      Prestin is critical to OHC somatic motility and hearing sensitivity in mammals. Several mutations of the human SLC26A5 gene have been associated with deafness. However, whether the IVS2-2A>G mutation in the human SLC26A5 gene causes deafness remains controversial. In this study, we created a mouse model in which the IVS2-2A>G mutation was introduced into the mouse Slc26a5 gene by gene targeting. The homozygous Slc26a5 mutant mice were viable and fertile and displayed normal hearing sensitivity by ABR threshold analysis. Whole-mount immunostaining using prestin antibody demonstrated that prestin was correctly targeted to the lateral wall of OHCs, and no obvious hair cell loss occurred in mutant mice. No significant difference in the amount of prestin protein was observed between mutants and controls using western blot analysis. In OHCs isolated from mutants, the NLC was also normal. However, we observed a splicing abnormality in the Slc26a5 mRNA of the mutant mice. Eleven nucleotides were missing from the 5' end of exon 3 in Slc26a5 mRNA, but the normal ATG start codon in exon 3 was still detected. Thus, the IVS2-2A>G mutation in the Slc26a5 gene is insufficient to cause hearing loss in mice.

      PubDate: 2016-05-15T17:31:07Z
      DOI: 10.1016/j.mrfmmm.2016.05.004
      Issue No: Vol. 790 (2016)
  • Site-directed mutants of human RECQ1 reveal functional importance of the
           zinc binding domain
    • Authors: Furqan Sami; Ronald K. Gary; Yayin Fang; Sudha Sharma
      Pages: 8 - 18
      Abstract: Publication date: Available online 17 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Furqan Sami, Ronald K. Gary, Yayin Fang, Sudha Sharma
      RecQ helicases are a highly conserved family of ATP-dependent DNA-unwinding enzymes with key roles in DNA replication and repair in all kingdoms of life. The RECQ1 gene encodes the most abundant RecQ homolog in humans. Mutations in RECQ1 significantly increase breast cancer susceptibility. We engineered full-length RECQ1 harboring point mutations in the zinc-binding motif (amino acids 419-480) within the conserved RecQ-specific- C-terminal (RQC) domain known to be critical for diverse biochemical and cellular functions of RecQ helicases. Wild-type RECQ1 contains a zinc ion. Substitution of three of the four conserved cysteine residues that coordinate zinc severely impaired the ATPase and DNA unwinding activities but retained DNA binding and single strand DNA annealing activities. Furthermore, alteration of these residues attenuated zinc binding and significantly changed the overall conformation of full-length RECQ1 protein. In contrast, substitution of cysteine residue at position 471 resulted in a wild-type like RECQ1 protein. Differential contribution of the conserved cysteine residues to the structure and functions of the RECQ1 protein is also inferred by homology modeling. Overall, our results indicate that the zinc binding motif in the RQC domain of RECQ1 is a key structural element that is essential for the structure-functions of RECQ1. Given the recent association of RECQ1 mutations with breast cancer, these observations will contribute to understanding the molecular basis of RECQ1 functions in cancer etiology.

      PubDate: 2016-05-20T17:52:07Z
      DOI: 10.1016/j.mrfmmm.2016.05.005
      Issue No: Vol. 790 (2016)
  • Induction of Genomic Instability and Activation of Autophagy in Artificial
           Human Aneuploid Cells
    • Authors: Kentaro Ariyoshi; Tomisato Miura; Kosuke Kasai; Yohei Fujishima; Mitsuo Oshimura; Mitsuaki A. Yoshida
      Pages: 19 - 30
      Abstract: Publication date: Available online 14 June 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Kentaro Ariyoshi, Tomisato Miura, Kosuke Kasai, Yohei Fujishima, Mitsuo Oshimura, Mitsuaki A. Yoshida
      Chromosome missegregation can lead to a change in chromosome number known as aneuploidy. Although aneuploidy is a known hallmark of cancer cells, the various mechanisms by which altered gene and/or DNA copy number facilitate tumorigenesis remain unclear. To understand the effect of aneuploidy occurring in non-tumorigenic human breast epithelial cells, we generated clones harboring artificial aneuploidy using microcell-mediated chromosome transfer. Our results demonstrate that clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. Also, the increased autophagy was observed in the artificially aneuploidy clones, and inhibition of autophagy resulted in increased genomic instability and DNA damage. In addition, the intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones, and inhibition of autophagy further increased the production of reactive oxygen species. Together, these results suggest that even a single extraneous chromosome can induce genomic instability, and that autophagy triggered by aneuploidy-induced stress is a mechanism to protect cells bearing abnormal chromosome number.

      PubDate: 2016-06-15T21:05:51Z
      DOI: 10.1016/j.mrfmmm.2016.06.001
      Issue No: Vol. 790 (2016)
  • The PARP inhibitor PJ-34 sensitizes cells to UVA-induced phototoxicity by
           a PARP independent mechanism
    • Authors: Petra Lakatos; Csaba Hegedűs; Nerea Salazar Ayestarán; Ángeles Juarranz; Katalin E. Kövér; Éva Szabó; László Virág
      Pages: 31 - 40
      Abstract: Publication date: Available online 5 July 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Petra Lakatos, Csaba Hegedűs, Nerea Salazar Ayestarán, Ángeles Juarranz, Katalin E. Kövér, Éva Szabó, László Virág
      A combination of a photosensitizer with light of matching wavelength is a common treatment modality in various diseases including psoriasis, atopic dermatitis and tumors. DNA damage and production of reactive oxygen intermediates may impact pathological cellular functions and viability. Here we set out to investigate the role of the nuclear DNA nick sensor enzyme poly(ADP-ribose) polymerase 1 in photochemical treatment (PCT)-induced tumor cell killing. We found that silencing PARP-1 or inhibition of its enzymatic activity with Veliparib had no significant effect on the viability of A431 cells exposed to 8-methoxypsoralen (8-MOP) and UVA (2.5J/cm2) indicating that PARP-1 is not likely to be a key player in either cell survival or cell death of PCT-exposed cells. Interestingly, however, another commonly used PARP inhibitor PJ-34 proved to be a photosensitizer with potency equal to 8-MOP. Irradiation of PJ-34 with UVA caused changes both in the UV absorption and in the 1H NMR spectra of the compound with the latter suggesting UVA-induced formation of tautomeric forms of the compound. Characterization of the photosensitizing effect revealed that PJ–34+UVA triggers overproduction of reactive oxygen species, induces DNA damage, activation of caspase 3 and caspase 8 and internucleosomal DNA fragmentation. Cell death in this model could not be prevented by antioxidants (ascorbic acid, trolox, glutathione, gallotannin or cell permeable superoxide dismutase or catalase) but could be suppressed by inhibitors of caspase-3 and −8. In conclusion, PJ-34 is a photosensitizer and PJ–34+UVA causes DNA damage and caspase-mediated cell death independently of PARP-1 inhibition.
      Graphical abstract image

      PubDate: 2016-07-08T05:05:07Z
      DOI: 10.1016/j.mrfmmm.2016.07.001
      Issue No: Vol. 790 (2016)
  • A novel papillation assay for the identification of genes affecting
           mutation rate in Pseudomonas putida and other pseudomonads
    • Authors: Mari Tagel; Kairi Tavita; Rita Hõrak; Maia Kivisaar; Heili Ilves
      Pages: 41 - 55
      Abstract: Publication date: Available online 6 July 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mari Tagel, Kairi Tavita, Rita Hõrak, Maia Kivisaar, Heili Ilves
      Formation of microcolonies (papillae) permits easy visual screening of mutational events occurring in single colonies of bacteria. In this study, we have established a novel papillation assay employable in a wide range of pseudomonads including Pseudomonas aeruginosa and Pseudomonas putida for monitoring mutation frequency in distinct colonies. With the aid of this assay, we conducted a genome-wide search for the factors affecting mutation frequency in P. putida. Screening ∼27,000 transposon mutants for increased mutation frequency allowed us to identify 34 repeatedly targeted genes. In addition to genes involved in DNA replication and repair, we identified genes participating in metabolism and transport of secondary metabolites, cell motility, and cell wall synthesis. The highest effect on mutant frequency was observed when truA (tRNA pseudouridine synthase), mpl (UDP-N-acetylmuramate-alanine ligase) or gacS (multi-sensor hybrid histidine kinase) were inactivated. Inactivation of truA elevated the mutant frequency only in growing cells, while the deficiency of gacS affected mainly stationary-phase mutagenesis. Thus, our results demonstrate the feasibility of the assay for isolating mutants with elevated mutagenesis in growing as well as stationary-phase bacteria.
      Graphical abstract image

      PubDate: 2016-07-08T05:05:07Z
      DOI: 10.1016/j.mrfmmm.2016.06.002
      Issue No: Vol. 790 (2016)
  • UV-C-Induced alleviation of transcriptional gene silencing through
           plant–plant communication: Key roles of jasmonic acid and salicylic acid
    • Authors: Wei Xu; Ting Wang; Shaoxin Xu; Fanghua Li; Chenguang Deng; Lijun Wu; Yuejin Wu; Po Bian
      Pages: 56 - 67
      Abstract: Publication date: Available online 27 April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Wei Xu, Ting Wang, Shaoxin Xu, Fanghua Li, Chenguang Deng, Lijun Wu, Yuejin Wu, Po Bian
      Plant stress responses at the epigenetic level are expected to allow more permanent changes of gene expression and potentially long-term adaptation. While it has been reported that plants subjected to adverse environments initiate various stress responses in their neighboring plants, little is known regarding epigenetic responses to external stresses mediated by plant–plant communication. In this study, we show that DNA repetitive elements of Arabidopsis thaliana, whose expression is inhibited epigenetically by transcriptional gene silencing (TGS) mechanism, are activated by UV-C irradiation through airborne plant–plant and plant–plant–plant communications, accompanied by DNA demethylation at CHH sites. Moreover, the TGS is alleviated by direct treatments with exogenous methyl jasmonate (MeJA) and methyl salicylate (MeSA). Further, the plant–plant and plant–plant–plant communications are blocked by mutations in the biosynthesis or signaling of jasmonic acid (JA) or salicylic acid (SA), indicating that JA and SA pathways are involved in the interplant communication for epigenetic responses. For the plant–plant–plant communication, stress cues are relayed to the last set of receiver plants by promoting the production of JA and SA signals in relaying plants, which exhibit upregulated expression of genes for JA and SA biosynthesis and enhanced emanation of MeJA and MeSA.

      PubDate: 2016-05-02T15:36:53Z
      DOI: 10.1016/j.mrfmmm.2016.04.003
      Issue No: Vol. 790 (2016)
  • Signaling factors and pathways of α-particle irradiation induced
           bilateral bystander responses between Beas-2B and U937 cells
    • Authors: Jiamei Fu; Juan Wang; Xiangdong Wang; Ping Wang; Jinping Xu; Cuiping Zhou; Yang Bai; Chunlin Shao
      Pages: 1 - 8
      Abstract: Publication date: Available online 2 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jiamei Fu, Juan Wang, Xiangdong Wang, Ping Wang, Jinping Xu, Cuiping Zhou, Yang Bai, Chunlin Shao
      Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral bystander responses that the release of TNF-α and IL-8 regulated by MAPK and NF-κB pathways synergistically increased cellular injury after α-particle irradiation.

      PubDate: 2016-05-02T15:36:53Z
      DOI: 10.1016/j.mrfmmm.2016.04.004
      Issue No: Vol. 789 (2016)
  • Different repair kinetic of DSBs induced by mitomycin C in peripheral
           lymphocytes of obese and normal weight adolescents
    • Authors: Alessia Azzarà; Chiara Pirillo; Caterina Giovannini; Giovanni Federico; Roberto Scarpato
      Pages: 9 - 14
      Abstract: Publication date: Available online 3 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Alessia Azzarà, Chiara Pirillo, Caterina Giovannini, Giovanni Federico, Roberto Scarpato
      In 2013, 42 million children under the age of 5 years were overweight or obese. In the context of obesity, we recently showed that (1) peripheral lymphocytes of obese children/adolescents had an 8-fold increase in double strand breaks (DSBs), expressed as g-H2AX foci, than normal weight adolescents, and (2) 30% of the damage was retained into chromosome mutations. Thus, we investigated DSBs repair efficiency in a group of obese adolescents assessing the kinetic of H2AX phosphorylation in mitomycin C (MMC)-treated lymphocytes harvested 2 h- or 4 h-post mutagen treatment. According to our previous studies, these harvesting times represent the peak of DSBs induction and the time in which an appreciable DSBs reduction was observed. In addition, we evaluated the expression of the high mobility group box-1 protein (HMGB1), a chromatin remodelling protein involved in DSBs repair and obesity. Compared to normal weight adolescents, obese subjects 1) showed higher levels of g-H2AX foci at either 2 h- (0.239±0.041 vs. 0.473±0.048, P=0.0016) or 4 h- (0.150±0.026 vs. 0.255±0.030, P=0.0198) post mutagen treatment, and 2) have repaired a greater amount of the initial lesions (0.088±0.033 vs. 0.218±0.045, P=0.0408). Concordantly, 1) HMGB1 levels of obese individuals increased and decreased at 2h- or 4 h-post mutagen treatment, respectively, and 2) the opposite occurred for the normal weight adolescents where the protein was down-expressed at 2h and over-expressed at 4h. In conclusion, lymphocytes of obese and normal weight adolescents showed a distinct temporal kinetic of repairing MMC-induced DSBs, together with a different expression of HMGB1. The finding that obesity may modulate the repair of DNA damage induced in lymphocytes by genotoxic agents should be confirmed by further experiments.

      PubDate: 2016-05-06T16:08:59Z
      DOI: 10.1016/j.mrfmmm.2016.05.001
      Issue No: Vol. 789 (2016)
  • Nucleotide excision repair deficiency increases levels of acrolein-derived
           cyclic DNA adduct and sensitizes cells to apoptosis induced by
           docosahexaenoic acid and acrolein
    • Authors: Jishen Pan; Elizabeth Sinclair; Zhuoli Xuan; Marcin Dyba; Ying Fu; Supti Sen; Deborah Berry; Karen Creswell; Jiaxi Hu; Rabindra Roy; Fung-Lung Chung
      Pages: 33 - 38
      Abstract: Publication date: Available online 16 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jishen Pan, Elizabeth Sinclair, Zhuoli Xuan, Marcin Dyba, Ying Fu, Supti Sen, Deborah Berry, Karen Creswell, Jiaxi Hu, Rabindra Roy, Fung-Lung Chung
      The acrolein derived cyclic 1,N2-propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT–116+ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA.

      PubDate: 2016-03-17T05:55:03Z
      DOI: 10.1016/j.mrfmmm.2016.02.011
      Issue No: Vol. 789 (2016)
  • Vincristine-induced bystander effect in human lymphocytes
    • Authors: Serena Testi; Alessia Azzarà; Caterina Giovannini; Sara Lombardi; Simona Piaggi; Maria Sole Facioni; Roberto Scarpato
      Pages: 39 - 47
      Abstract: Publication date: Available online 25 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Serena Testi, Alessia Azzarà, Caterina Giovannini, Sara Lombardi, Simona Piaggi, Maria Sole Facioni, Roberto Scarpato
      Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5±1.41at 6μM, 22±2.12at 12μM or 28.25±5.13at 15μM vs. a control value of 4.75±1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75±0.88at 0.0μM, 27.25±2.30at 0.4μM, 46.25±1.94at 0.8μM, 98.25±7.25at 1.6μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the bystander effect induced by VCR. In fact, we observed an increased level of ROS, IL-32 and TGF-β in the CM from VCR treated cultures, not present in MMC treated cultures.

      PubDate: 2016-03-26T08:06:02Z
      DOI: 10.1016/j.mrfmmm.2016.03.001
      Issue No: Vol. 789 (2016)
  • Simple sequence repeat variations expedite phage divergence: mechanisms of
           indels and gene mutations
    • Authors: Tiao-Yin Lin
      Pages: 48 - 56
      Abstract: Publication date: Available online 14 April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Tiao-Yin Lin
      Phages are the most abundant biological entities and influence prokaryotic communities on Earth. Comparing closely related genomes sheds light on molecular events shaping phage evolution. Simple sequence repeat (SSR) variations impart over half of the genomic changes between T7M and T3, indicating an important role of SSRs in accelerating phage genetic divergence. Differences in coding and noncoding regions of phages infecting different hosts, coliphages T7M and T3, Yersinia phage φYeO3-12, and Salmonella phage φSG-JL2, frequently arise from SSR variations. Such variations modify noncoding and coding regions; the latter efficiently changes multiple amino acids, thereby hastening protein evolution. Four classes of events are found to drive SSR variations: insertion/deletion of SSR units, expansion/contraction of SSRs without alteration of genome length, changes of repeat motifs, and generation/loss of repeats. The categorization demonstrates the ways SSRs mutate in genomes during phage evolution. Indels are common constituents of genome variations and human diseases, yet, how they occur without preexisting repeat sequence is less understood. Non-repeat-unit-based misalignment-elongation (NRUBME) is proposed to be one mechanism for indels without adjacent repeats. NRUBME or consecutive NRUBME may also change repeat motifs or generate new repeats. NRUBME invoking a non-Watson-Crick base pair explains insertions that initiate mononucleotide repeats. Furthermore, NRUBME successfully interprets many inexplicable human di- to tetranucleotide repeat generations. This study provides the first evidence of SSR variations expediting phage divergence, and enables insights into the events and mechanisms of genome evolution. NRUBME allows us to emulate natural evolution to design indels for various applications.
      Graphical abstract image

      PubDate: 2016-04-19T12:24:26Z
      DOI: 10.1016/j.mrfmmm.2016.04.001
      Issue No: Vol. 789 (2016)
  • Sample size determination for the fluctuation experiment
    • Authors: Zheng
      Abstract: Publication date: Available online 19 December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Qi Zheng
      The Luria-Delbrück fluctuation experiment protocol is increasingly employed to determine microbial mutation rates in the laboratory. An important question raised at the planning stage is “How many cultures are needed'” For over 70 years sample sizes have been determined either by intuition or by following published examples where sample sizes were chosen intuitively. This paper proposes a practical method for determining the sample size. The proposed method relies on existing algorithms for computing the expected Fisher information under two commonly used mutant distributions. The role of partial plating in reducing sample size is discussed.

      PubDate: 2016-12-22T17:47:45Z
    • Abstract: Publication date: November–December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 793–794

      PubDate: 2016-11-30T16:08:07Z
  • Influence of reduced glutathione on end-joining of DNA double-strand
           breaks: Cytogenetical and molecular approach
    • Authors: Nitin Ghoshal; Sheetal Sharma; Atanu Banerjee; Sillarine Kurkalang; Sathees C Raghavan; Anupam Chatterjee
      Abstract: Publication date: Available online 9 November 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Nitin Ghoshal, Sheetal Sharma, Atanu Banerjee, Sillarine Kurkalang, Sathees C Raghavan, Anupam Chatterjee
      Radiation induced DNA double-strand breaks (DSB) are the major initial lesions whose misrejoining may lead to exchange aberrations. However, the role of glutathione (GSH), a major cellular thiol, in regulating cell’s sensitivity to DNA damaging agents is not well understood. Influence of endogenous GSH on the efficiency of X-rays and bleomycin (Blem) induced DNA DSBs end-joining has been tested here cytogenetically, in human lymphocytes and Hct116 cells. In another approach, oligomeric DNA (75bp) containing 5′-compatible and non-compatible overhangs mimicking the endogenous DSB were for rejoining in presence of cell-free extracts from cells having different endogenous GSH levels. Frequency of aberrations, particularly exchange aberrations, was significantly increased when Blem was combined with radiation. The exchange aberration frequency was further enhanced when combined treatment was given at 4°C since DNA lesions are poorly repaired at 4°C so that a higher number of DNA breaks persist and interact when shifted from 4°C to 37°C. The exchange aberrations increased further when the combined treatment was given to Glutathione-ester (GE) pre-treated cells, indicating more frequent rejoining of DNA lesions in presence of higher cellular GSH. This is further supported by the drastic reduction in frequency of exchange aberrations but significant increase in incidences of deletions when combined treatment was given to GSH-depleted cells. End-joining efficiency of DNA DSBs with compatible ends was better than for non-compatible ends. End-joining efficiency of testicular and MCF7 cell extracts was better than that of lungs and Hct116 cells. Cell extract made from GE-treated MCF-7 cells provided more efficient end-joining than from untreated and GSH-depleted cells. However, direct addition of GSH to the cell-free extracts showed considerable reduction in end-joining efficiency. Present data indicate that higher endogenous GSH favours rejoining of DNA DSBs (both restitution and illegitimate reunion) which in turn produce more exchange aberrations.

      PubDate: 2016-11-10T11:15:49Z
      DOI: 10.1016/j.mrfmmm.2016.10.005
  • Transposon-mediated activation of the Escherichia coli glpFK operon is
           inhibited by specific DNA-binding proteins: Implications for
           stress-induced transposition events
    • Authors: Zhongge Zhang; Milton Saier
      Abstract: Publication date: November–December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 793–794
      Author(s): Zhongge Zhang, Milton H. Saier
      Escherichia coli cells deleted for the cyclic AMP (cAMP) receptor protein (Crp) gene (Δcrp) cannot utilize glycerol because cAMP-Crp is a required activator of the glycerol utilization operon, glpFK. We have previously shown that a transposon, Insertion Sequence 5 (IS5), can insert into the upstream regulatory region of the operon to activate the glpFK promoter and enable glycerol utilization. GlpR, which represses glpFK transcription, binds to the glpFK upstream region near the site of IS5 insertion and inhibits insertion. By adding cAMP to the culture medium in ΔcyaA cells, we here show that the cAMP-Crp complex, which also binds to the glpFK upstream regulatory region, inhibits IS5 hopping into the activating site. Control experiments showed that the frequencies of mutations in response to cAMP were independent of parental cell growth rate and the selection procedure. These findings led to the prediction that glpFK-activating IS5 insertions can also occur in wild-type (Crp+) cells under conditions that limit cAMP production. Accordingly, we found that IS5 insertion into the activating site in wild-type cells is elevated in the presence of glycerol and a non-metabolizable sugar analogue that lowers cytoplasmic cAMP concentrations. The resultant IS5 insertion mutants arising in this minimal medium become dominant constituents of the population after prolonged periods of growth. The results show that DNA binding transcription factors can reversibly mask a favored transposon target site, rendering a hot spot for insertion less favored. Such mechanisms could have evolved by natural selection to overcome environmental adversity.

      PubDate: 2016-11-03T09:09:06Z
  • Cell-free nucleic acids as continuously arising endogenous DNA mutagens: A
           new proposal
    • Authors: Ranjan Basak; Naveen Kumar Nair; Indraneel Mittra
      Abstract: Publication date: Available online 12 October 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ranjan Basak, Naveen Kumar Nair, Indraneel Mittra
      There is extensive literature to show that nucleic acids can be taken up by cells under experimental conditions and that foetal DNA can be detected in maternal tissues. The uptaken DNA can integrate into host cell genomes and can be transcribed and translated into proteins. They can also cause chromosomal damage and karyotype alterations. Cell-free nucleic acids (cfNAs)-based non-invasive DNA diagnostic techniques are being extensively researched in the field of cancer with the potential to advance new prognostic parameters and direct treatment decisions. However, whether extracellular cfNAs that are released into circulation from dying cells as a consequence of normal physiology have any functional significance has not been explored. A recent study has demonstrated that circulating cfNAs have the ability to cause DNA damage and mutagenesis by illegitimately integrating into healthy cells of the body, thereby acting as mobile genetic elements. Fluorescently-labeled cfNAs isolated from sera of cancer patients and healthy volunteers were shown to be readily taken up by host cells followed by activation of a DNA-damage-repair-response which led their large scale integration into the host cell genomes. The latter caused dsDNA breaks and apoptosis in cells in vitro and in those of vital organs when injected intravenously into mice. Cell-free chromatin was consistently more active than cell-free DNA, while cfNAs derived from cancer patients were significantly more active than those from healthy volunteers. This study suggests that circulating extracellular cfNAs act as physiological continuously arising DNA mutagens with implications for ageing, cancer and a host of other degenerative human pathologies.

      PubDate: 2016-10-14T04:49:43Z
      DOI: 10.1016/j.mrfmmm.2016.10.002
    • Abstract: Publication date: September–October 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 791–792

      PubDate: 2016-10-14T04:49:43Z
    • Abstract: Publication date: August 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 790

      PubDate: 2016-07-29T15:05:45Z
    • Abstract: Publication date: July 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 789

      PubDate: 2016-05-30T18:44:40Z
    • Abstract: Publication date: June 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 788

      PubDate: 2016-05-30T18:44:40Z
  • Chromothripsis and Epigenetics in the Heritable Genotoxicity,
           Carcinogenicity and Fetotoxicity of Cannabis and Other Addictions.
    • Authors: Albert Stuart; Reece Gary Kenneth Hulse
      Abstract: Publication date: Available online 4 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Albert Stuart Reece, Gary Kenneth Hulse
      The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule machinery of the mitotic spindle followed by haphazard chromosomal annealing, together with sophisticated insights from epigenetics, provide profound mechanistic insights into some of the most perplexing classical observations of addiction medicine, including cancerogenesis, the younger and aggressive onset of addiction-related carcinogenesis, the heritability of addictive neurocircuitry and cancers, and foetal malformations. Tetrahydrocannabinol (THC) and other addictive agents have been shown to inhibit tubulin polymerization which perturbs the formation and function of the microtubules of the mitotic spindle. This disruption of the mitotic machinery perturbs proper chromosomal segregation during anaphase and causes micronucleus formation which is the primary locus and cause of the chromosomal pulverization of chromothripsis and downstream genotoxic events including oncogene induction and tumour suppressor silencing. Moreover the complementation of multiple positive cannabis-cancer epidemiological studies, and replicated dose-response relationships with established mechanisms fulfils causal criteria. This information is also consistent with data showing acceleration of the aging process by drugs of addiction including alcohol, tobacco, cannabis, stimulants and opioids. THC shows a non-linear sigmoidal dose-response relationship in multiple pertinent in vitro and preclinical genotoxicity assays, and in this respect is similar to the serious major human mutagen thalidomide. Rising community exposure, tissue storage of cannabinoids, and increasingly potent phytocannabinoid sources, suggests that the threshold mutagenic dose for cancerogenesis will increasingly be crossed beyond the developing world, and raise transgenerational transmission of teratogenicity as an increasing concern.
      Graphical abstract image

      PubDate: 2016-05-06T16:08:59Z
  • Gene Mutations in Rats with Moderate Malnutrition
    • Authors: M.Monserrat Edith; Elsa del Carmen Leonor
      Abstract: Publication date: Available online 8 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): M.Monserrat Pacheco-Martínez, Edith Cortés-Barberena, Elsa Cervantes-Ríos, María del Carmen García-Rodríguez, Leonor Rodríguez-Cruz, Rocío Ortiz-Muñiz
      The relationship between malnutrition and genetic damage has been widely studied in human and animal models, leading to the observation that interactions between genotoxic exposure and micronutrient status appear to affect genomic stability. A new assay has been developed that uses the phosphatidylinositol glycan class A gene (Pig-a) as a reporter for measuring in vivo gene mutation. The Pig-a assay can be employed to evaluate mutant frequencies (MFs) in peripheral blood reticulocytes (RETs) and erythrocytes (RBCs) using flow cytometry. In the present study, we assessed the effects of malnutrition on mutagenic susceptibility by exposing undernourished (UN) and well-nourished (WN) rats to N-ethyl-N-nitrosourea (ENU) and measuring Pig-a MFs. Two week-old UN and WN male Han-Wistar rats were treated daily with 0, 20, or 40mg/kg ENU for 3 consecutive days. Blood was collected from the tail vein one day before ENU treatment (Day −1) and after ENU administration on Days 7, 14, 21, 28, 35, 42, 49, 56 and 63. Pig-a MFs were measured in RETs and RBCs as the RETCD59− and RBCCD59− frequencies. In the vehicle control groups, the frequencies of mutant RETs and RBCs were significantly higher in UN rats compared with WN rats at all sampling times. The ENU treatments increased RET and RBC MFs starting at Day 7. Although ENU-induced Pig-a MFs were consistently lower in UN rats than in WN rats, these differences were not significant. To understand these responses, further studies should use other mutagens and nucleated surrogate cells and examine the types of mutations induced in UN and WN rats.

      PubDate: 2016-03-13T16:51:39Z
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