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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  [3039 journals]
  • 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)
  • Induction of the Long Noncoding RNA NBR2 from the Bidirectional BRCA1
           Promoter Under Hypoxic Conditions
    • 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
  • Modulation of Modeled Microgravity on Radiation-Induced Adaptive Response
           of Root Growth in Arabidopsis thaliana
    • 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
  • Cyto-genotoxic and DNA methylation changes induced by different crystal
           phases of TiO2-np in bronchial epithelial (16-HBE) cells
    • 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
    • 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)
  • Editorial
    • Authors: Paul Hasty
      First page: 1
      Abstract: Publication date: June 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 788
      Author(s): Paul Hasty

      PubDate: 2016-05-30T18:44:40Z
      DOI: 10.1016/j.mrfmmm.2016.05.003
      Issue No: Vol. 788 (2016)
  • DNA double strand break repair, aging and the chromatin connection
    • Authors: Vera Gorbunova; Andrei Seluanov
      Pages: 2 - 6
      Abstract: Publication date: Available online 15 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Vera Gorbunova, Andrei Seluanov
      Are DNA damage and mutations possible causes or consequences of aging' This question has been hotly debated by biogerontologists for decades. The importance of DNA damage as a possible driver of the aging process went from being widely recognized to then forgotten, and is now slowly making a comeback. DNA double strand breaks (DSBs) are particularly relevant to aging because of their toxicity, increased frequency with age and the association of defects in their repair with premature aging. Recent studies expand the potential impact of DNA damage and mutations on aging by linking DNA DSB repair and age-related chromatin changes. There is overwhelming evidence that increased DNA damage and mutations accelerate aging. However, an ultimate proof of causality would be to show that enhanced genome and epigenome stability delays aging. This is not an easy task, as improving such complex biological processes is infinitely more difficult than disabling it. We will discuss the possibility that animal models with enhanced DNA repair and epigenome maintenance will be generated in the near future.

      PubDate: 2016-02-18T03:19:08Z
      DOI: 10.1016/j.mrfmmm.2016.02.004
      Issue No: Vol. 788 (2016)
  • FANCJ at the FORK
    • Authors: Sharon B. Cantor; Sumeet Nayak
      Pages: 7 - 11
      Abstract: Publication date: Available online 17 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Sharon B. Cantor, Sumeet Nayak

      PubDate: 2016-02-18T03:19:08Z
      DOI: 10.1016/j.mrfmmm.2016.02.003
      Issue No: Vol. 788 (2016)
  • Genomic stability during cellular reprogramming: mission impossible'
    • Authors: Mathieu von Joest; Sabela Búa Aguín; Han Li
      Pages: 12 - 16
      Abstract: Publication date: Available online 20 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mathieu von Joest, Sabela Bua, Han Li
      The generation of induced pluripotent stem cells (iPSCs) from adult somatic cells is one of the most exciting discoveries in recent biomedical research. It holds tremendous potential in drug discovery and regenerative medicine. However, a series of reports highlighting genomic instability in iPSCs raises concerns about their clinical application. Although the mechanisms cause genomic instability during cellular reprogramming are largely unknown, several potential sources have been suggested. This review summarizes current knowledge on this active research field and discusses the latest efforts to alleviate the genomic insults during cellular reprogramming to generate iPSCs with enhanced quality and safety.

      PubDate: 2016-01-24T20:10:29Z
      DOI: 10.1016/j.mrfmmm.2016.01.001
      Issue No: Vol. 788 (2016)
  • Risky Business: Microhomology-Mediated End Joining
    • Authors: Supriya Sinha; Diana Villarreal; Eun Yong Shim; Sang Eun Lee
      Pages: 17 - 24
      Abstract: Publication date: Available online 2 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Supriya Sinha, Diana Villarreal, Eun Yong Shim, Sang Eun Lee
      Prevalence of microhomology (MH) at the breakpoint junctions in somatic and germ-line chromosomal rearrangements and in the programed immune receptor rearrangements from cells deficient in classical end joining reveals an enigmatic process called MH-mediated end joining (MMEJ). MMEJ repairs DNA double strand breaks (DSBs) by annealing flanking MH and deleting genetic information at the repair junctions from yeast to humans. Being genetically distinct from canonical DNA DSB pathways, MMEJ is involved with the fusions of eroded/uncapped telomeres as well as with the assembly of chromosome fragments in chromothripsis. In this review article, we will discuss an up-to-date model representing the MMEJ process and the mechanism by which cells regulate MMEJ to limit repair-associated mutagenesis. We will also describe the possible therapeutic gains resulting from the inhibition of MMEJ in recombination deficient cancers. Lastly, we will embark on two contentious issues associated with MMEJ such as the significance of MH at the repair junction to be the hallmark of MMEJ and the relationship of MMEJ to other mechanistically related DSB repair pathways.

      PubDate: 2016-01-03T10:26:15Z
      DOI: 10.1016/j.mrfmmm.2015.12.005
      Issue No: Vol. 788 (2016)
  • Reprint of “DNA, the central molecule of aging”
    • Authors: Peter Lenart; Lumir Krejci
      Pages: 25 - 31
      Abstract: Publication date: Available online 28 April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Peter Lenart, Lumir Krejci
      Understanding the molecular mechanism of aging could have enormous medical implications. Despite a century of research, however, there is no universally accepted theory regarding the molecular basis of aging. On the other hand, there is plentiful evidence suggesting that DNA constitutes the central molecule in this process. Here, we review the roles of chromatin structure, DNA damage, and shortening of telomeres in aging and propose a hypothesis for how their interplay leads to aging phenotypes.

      PubDate: 2016-05-02T15:36:53Z
      DOI: 10.1016/j.mrfmmm.2016.04.002
      Issue No: Vol. 788 (2016)
  • Charged Particle Mutagenesis at Low Dose and Fluence in Mouse Splenic T
    • Authors: Dmytro Grygoryev; Stacey Gauny; Michael Lasarev; Anna Ohlrich; Amy Kronenberg; Mitchell S. Turker
      Pages: 32 - 40
      Abstract: Publication date: Available online 29 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Dmytro Grygoryev, Stacey Gauny, Michael Lasarev, Anna Ohlrich, Amy Kronenberg, Mitchell S. Turker
      High-energy heavy charged particles (HZE ions) found in the deep space environment can significantly affect human health by inducing mutations and related cancers. To better understand the relation between HZE ion exposure and somatic mutation, we examined cell survival fraction, Aprt mutant frequencies, and the types of mutations detected for mouse splenic T cells exposed in vivo to graded doses of densely ionizing 48Ti ions (1GeV/amu, LET=107 keV/μm), 56Fe ions (1GeV/amu, LET=151 keV/μm) ions, or sparsely ionizing protons (1GeV, LET=0.24 keV/μm). The lowest doses for 48Ti and 56Fe ions were equivalent to a fluence of approximately 1 or 2 particle traversals per nucleus. In most cases, Aprt mutant frequencies in the irradiated mice were not significantly increased relative to the controls for any of the particles or doses tested at the pre-determined harvest time (3-5 months after irradiation). Despite the lack of increased Aprt mutant frequencies in the irradiated splenocytes, a molecular analysis centered on chromosome 8 revealed the induction of radiation signature mutations (large interstitial deletions and complex mutational patterns), with the highest levels of induction at 2 particles nucleus for the 48Ti and 56Fe ions. In total, the results show that densely ionizing HZE ions can induce characteristic mutations in splenic T cells at low fluence, and that at least a subset of radiation-induced mutant cells are stably retained despite the apparent lack of increased mutant frequencies at the time of harvest.

      PubDate: 2016-03-30T08:48:02Z
      DOI: 10.1016/j.mrfmmm.2016.03.004
      Issue No: Vol. 788 (2016)
  • Implications of genotypic differences in the generation of a urinary
           metabolomics radiation signature.
    • Authors: Evagelia C. Laiakis; Evan L. Pannkuk; Maria Elena Diaz-Rubio; Yi-Wen Wang; Tytus D. Mak; Cynthia M. Simbulan-Rosenthal; David J. Brenner; Albert J. Fornace
      Pages: 41 - 49
      Abstract: Publication date: Available online 25 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Evagelia C. Laiakis, Evan L. Pannkuk, Maria Elena Diaz-Rubio, Yi-Wen Wang, Tytus D. Mak, Cynthia M. Simbulan-Rosenthal, David J. Brenner, Albert J. Fornace
      The increased threat of radiological terrorism and accidental nuclear exposures, together with increased usage of radiation-based medical procedures, has made necessary the development of minimally invasive methods for rapid identification of exposed individuals. Genetically predisposed radiosensitive individuals comprise a significant number of the population and require specialized attention and treatments after such events. Metabolomics, the assessment of the collective small molecule content in a given biofluid or tissue has proven effective in the rapid identification of radiation biomarkers and metabolic perturbations. To investigate how the genotypic background may alter the ionizing radiation (IR) signature, we analyzed urine from Parp1−/− mice, as a model radiosensitive genotype, exposed to IR by utilizing the analytical power of liquid chromatography coupled with mass spectrometry (LC–MS), as urine has been thoroughly investigated in wild type (WT) mice in previous studies from our laboratory. Samples were collected at days one and three after irradiation, time points that are important for the early and efficient triage of exposed individuals. Time- dependent perturbations in metabolites were observed in the tricarboxylic acid pathway (TCA). Other differentially excreted metabolites included amino acids and metabolites associated with dysregulation of energy metabolism pathways. Time-dependent apoptotic pathway activation between WT and mutant mice following IR exposure may explain the altered excretion patterns, although the origin of the metabolites remains to be determined. This first metabolomics study in urine from radiation exposed genetic mutant animal models provides evidence that this technology can be used to dissect the effects of genotoxic agents on metabolism by assessing easily accessible biofluids and identify biomarkers of radiation exposure. Applications of metabolomics could be incorporated in the future to further elucidate the effects of IR on the metabolism of Parp1−/− genotype by assessing individual tissues.

      PubDate: 2016-03-26T08:06:02Z
      DOI: 10.1016/j.mrfmmm.2016.03.003
      Issue No: Vol. 788 (2016)
  • Lack of increased DNA double-strand breaks in peripheral blood mononuclear
           cells of individuals from high level natural radiation areas of Kerala
           coast in India
    • Authors: Vinay Jain; P.R. Vivek Kumar; P.K.M. Koya; G. Jaikrishan; Birajalaxmi Das
      Pages: 50 - 57
      Abstract: Publication date: Available online 25 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Vinay Jain, P.R.Vivek Kumar, P.K.M. Koya, G. Jaikrishan, Birajalaxmi Das
      The high level natural radiation area (HLNRA) of Kerala is a 55km long and 0.5km wide strip in south west coast of India. The level of background radiation in this area varies from<1.0mGy/year to 45.0mGy/year. It offers unique opportunity to study the effect of chronic low dose/low dose-rate radiation directly on human population. Spontaneous level of DNA double strand breaks (DSBs) was quantified in peripheral blood mononuclear cells of 91 random individuals from HLNRA (N=61, mean age: 36.1±7.43years) and normal level natural radiation area (NLNRA) (N=30, mean age: 35.5±6.35years) using gamma-H2AX as a marker. The mean annual dose received by NLNRA and HLNRA individuals was 1.28±0.086mGy/year and 8.28±4.96mGy/year, respectively. The spontaneous frequency of DSBs in terms of gamma-H2AX foci among NLNRA and HLNRA individuals were 0.095±0.009 and 0.084±0.004 per cell (P=0.22). The individuals from HLNRA were further classified as low dose group (LDG, 1.51-5.0mGy/year, mean dose: 2.63±0.76mGy/year) and high dose group (HDG,>5.0mGy/year, mean dose: 11.04±3.57mGy/year). The spontaneous frequency of gamma-H2AX foci per cell in NLNRA, LDG and HDG was observed to be 0.095±0.009, 0.096±0.008 and 0.078±0.004 respectively. Individuals belonging to HDG of HLNRA showed marginally lower frequency of DSBs as compared to NLNRA and LDG of HLNRA. This could be suggestive of either lower induction or better repair of DSBs in individuals from HDG of HLNRA. The present study indicated that 5.0mGy/year could be a possible threshold dose for DSB induction at chronic low-dose radiation exposure in vivo. However, further studies on DNA damage induction and repair kinetics are required to draw firm conclusions.

      PubDate: 2016-03-26T08:06:02Z
      DOI: 10.1016/j.mrfmmm.2016.03.002
      Issue No: Vol. 788 (2016)
  • Increased MTHFR promoter methylation in mothers of Down syndrome
    • Authors: Fabio Coppedè; Maria Denaro; Pierpaola Tannorella; Lucia Migliore
      Pages: 1 - 6
      Abstract: Publication date: Available online 22 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Fabio Coppedè, Maria Denaro, Pierpaola Tannorella, Lucia Migliore
      Despite that advanced maternal age at conception represents the major risk factor for the birth of a child with Down syndrome (DS), most of DS babies are born from women aging less than 35 years. Studies performed in peripheral lymphocytes of those women revealed several markers of global genome instability, including an increased frequency of micronuclei, shorter telomeres and impaired global DNA methylation. Furthermore, young mothers of DS individuals (MDS) are at increased risk to develop dementia later in life, suggesting that they might be “biologically older” than mothers of euploid babies of similar age. Mutations in folate pathway genes, and particularly in the methylenetetrahydrofolate reductase (MTHFR) one, have been often associated with maternal risk for a DS birth as well as with risk of dementia in the elderly. Recent studies pointed out that also changes in MTHFR methylation levels can contribute to human disease, but nothing is known about MTHFR methylation in MDS tissues. We investigated MTHFR promoter methylation in DNA extracted from perypheral lymphocytes of 40 MDS and 44 matched control women that coinceived their children before 35 years of age, observing a significantly increased MTHFR promoter methylation in the first group (33.3±8.1% vs. 28.3±5.8%; p =0.001). In addition, the frequency of micronucleated lymphocytes was available from the women included in the study, was higher in MDS than control mothers (16.1±8.6‰ vs. 10.5±4.3‰; p =0.0004), and correlated with MTHFR promoter methylation levels (r =0.33; p =0.006). Present data suggest that MTHFR epimutations are likely to contribute to the increased genomic instability observed in cells from MDS, and could play a role in the risk of birth of a child with DS as well as in the onset of age related diseases in those women.

      PubDate: 2016-02-27T08:44:12Z
      DOI: 10.1016/j.mrfmmm.2016.02.008
      Issue No: Vol. 787 (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
    • Abstract: Publication date: May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 787

      PubDate: 2016-04-09T10:34:02Z
  • 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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