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Journal Cover Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
  [SJR: 1.897]   [H-I: 136]   [4 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0027-5107
   Published by Elsevier Homepage  [3043 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)
       
  • 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: 2017-08-14T16:48:48Z
      DOI: 10.1016/j.mrfmmm.2016.10.001
      Issue No: Vol. 793-794 (2017)
       
  • Evidence for cell-free nucleic acids as continuously arising endogenous
           DNA mutagens
    • Authors: Ranjan Basak; Naveen Kumar Nair; Indraneel Mittra
      Pages: 15 - 21
      Abstract: Publication date: November–December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 793–794
      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: 2017-08-14T16:48:48Z
      DOI: 10.1016/j.mrfmmm.2016.10.002
      Issue No: Vol. 793-794 (2017)
       
  • 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: 2017-08-14T16:48:48Z
      DOI: 10.1016/j.mrfmmm.2016.10.004
      Issue No: Vol. 793-794 (2017)
       
  • 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: 2017-08-14T16:48:48Z
      DOI: 10.1016/j.mrfmmm.2016.11.001
      Issue No: Vol. 793-794 (2017)
       
  • Automatic detection of micronuclei by cell microscopic image processing
    • Authors: Mohammad Taghi Bahreyni Toossi; Hosein Azimian; Omid Sarrafzadeh; Shokoufeh Mohebbi; Shokouhozaman Soleymanifard
      Abstract: Publication date: Available online 12 August 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mohammad Taghi Bahreyni Toossi, Hosein Azimian, Omid Sarrafzadeh, Shokoufeh Mohebbi, Shokouhozaman Soleymanifard
      With the development and applications of ionizing radiation in medicine, the radiation effects on human health get more and more attention. Ionizing radiation can lead to various forms of cytogenetic damage, including increased frequencies of micronuclei (MNi) and chromosome abnormalities. The cytokinesis block micronucleus (CBMN) assay is widely used method for measuring MNi to determine chromosome mutations or genome instability in cultured human lymphocytes. The visual scoring of MNi is time-consuming and scorer fatigue can lead to inconsistency. In this work, we designed software for the scoring of in vitro CBMN assay for biomonitoring on Giemsa-stained slides that overcome many previous limitations. Automatic scoring proceeds in four stages as follows. First, overall segmentation of nuclei is done. Then, binucleated (BN) cells are detected. Next, the entire cell is estimated for each BN as it is assumed that there is no detectable cytoplasm. Finally, MNi are detected within each BN cell. The designed Software is even able to detect BN cells with vague cytoplasm and MNi in peripheral blood smear. Our system is tested on a self-provided dataset and is achieved high sensitivities of about 98% and 82% in recognizing BN cells and MNi, respectively. Moreover, in our study less than 1% false positives were observed that makes our system reliable for practical MNi scoring.

      PubDate: 2017-08-14T16:48:48Z
      DOI: 10.1016/j.mrfmmm.2017.07.012
       
  • Environmental mutagenesis and radiation biology: The legacy of William
           Morgan
    • Authors: Jeffrey L. Schwartz
      Abstract: Publication date: Available online 25 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jeffrey L. Schwartz
      A symposium entitled Environmental Mutagenesis and Radiation Biology was held on September 27, 2016 to honor the memory of Dr. William F. Morgan who passed away unexpectedly on November 13, 2015. The speakers presented the latest reviews on homologous recombination repair, induced genetic instability, bystander effects, and risk estimate development. Their presentations are presented following the introduction.

      PubDate: 2017-08-14T16:48:48Z
      DOI: 10.1016/j.mrfmmm.2017.07.009
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: November–December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 793–794


      PubDate: 2017-08-14T16:48:48Z
       
  • 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: 2017-08-14T16:48:48Z
       
  • Regulation of repair pathway choice at two-ended DNA double-strand breaks
    • Authors: Atsushi Shibata
      Abstract: Publication date: Available online 29 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Atsushi Shibata
      A DNA double-strand break (DSB) is considered to be a critical DNA lesion because its misrepair can cause severe mutations, such as deletions or chromosomal translocations. For the precise repair of DSBs, the repair pathway that is optimal for the particular circumstance needs to be selected. Non-homologous end joining (NHEJ) functions in G1/S/G2 phase, while homologous recombination (HR) becomes active only in S/G2 phase after DNA replication. DSB end structure is another factor affecting the repair pathway. For example, one-ended DSBs in S phase are mainly repaired by HR due to the lack of a partner DSB end for NHEJ. In contrast, two-ended DSBs, which are mainly induced by ionizing radiation, are repaired by either NHEJ or HR in G2 cells. Under the current model in terms of DSB repair pathway usage in G2 phase, NHEJ repairs ∼70% of two-ended DSBs, whereas HR repairs only ∼30%. Recent studies propose that NHEJ factors can bind all the DSB ends and are then either used to progress that pathway of DSB repair, or the repair proceeds by HR. In addition, molecular regulation by BRCA1 and 53BP1 has also been proposed. At DSB sites, BRCA1 functions to alleviate the 53BP1 barrier to resection by promoting 53BP1 dephosphorylation, followed by RIF1 release and 53BP1 repositioning. This timely 53BP1 repositioning may be important for the establishment of a chromatin environment that promotes the recruitment of EXO1 for resection in HR. This review summarizes current knowledge on factors regulating DSB repair pathway choice in terms of spatiotemporal regulation by focusing on the repair events at two-ended DSBs in G2 cells.

      PubDate: 2017-08-04T16:17:40Z
      DOI: 10.1016/j.mrfmmm.2017.07.011
       
  • Single nucleotide variations in cultured cancer cells: effect of mismatch
           repair
    • Authors: Igor G. Panyutin; Irina V. Panyutin; Ian Powell-Castilla; Laura Felix; Ronald D. Neumann
      Abstract: Publication date: Available online 27 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Igor G. Panyutin, Irina V. Panyutin, Ian Powell-Castilla, Laura Felix, Ronald D. Neumann
      We assessed single nucleotide variations (SNVs) between individual cells in two cancer cell lines; DU145, from brain metastasis of prostate tumor with deficient mismatch repair; and HT1080, a fibrosarcoma cell line. Clones of individual cells were isolated, and sequenced using Ion Ampliseq comprehensive cancer panel that covered the exomes of 409 oncogenes and tumor suppressor genes. Five clones of DU145 and four clones of HT1080 cells were analyzed. We found from 7 to 12 unique SNVs between DU145 clones, while HT1080 clones showed no more than one unique SNV. We then sub-cloned individual cells from some of these isolated clones of DU145 and HT1080 cells. The sub-clones were expanded from a single cell to approximately one million cells after about 20 cell divisions. The sub-clones of DU145 cells had from one to four new unique SNVs within the sequenced regions. No unique SNVs were found between sub-clones of HT1080 cells. Our data demonstrate that the extent of genetic variation at the single nucleotide level in cultured cancer cells is significantly affected by the status of the DNA mismatch repair system.
      Graphical abstract image

      PubDate: 2017-08-04T16:17:40Z
      DOI: 10.1016/j.mrfmmm.2017.07.003
       
  • Paths from DNA damage and signaling to genome rearrangements via
           homologous recombination
    • Authors: Jac A. Nickoloff
      Abstract: Publication date: Available online 24 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jac A. Nickoloff
      DNA damage is a constant threat to genome integrity. DNA repair and damage signaling networks play a central role maintaining genome stability, suppress tumorigenesis, and determine tumor response to common cancer chemotherapeutic agents and radiotherapy. DNA double-strand breaks (DSBs) are critical lesions induced by ionizing radiation and when replication forks encounter damage. DSBs can result in mutations and large-scale genome rearrangements reflecting mis-repair by non-homologous end joining or homologous recombination. Ionizing radiation induces genetic change immediately, and it also triggers delayed events weeks or even years after exposure, long after the initial damage has been repaired or diluted through cell division. This review covers DNA damage signaling and repair pathways and cell fate following genotoxic insult, including immediate and delayed genome instability and cell survival/cell death pathways.

      PubDate: 2017-07-25T15:27:57Z
      DOI: 10.1016/j.mrfmmm.2017.07.008
       
  • The Emerging Roles of the Ubiquitination/deubiquitination System in Tumor
           Radioresistance regarding DNA damage responses, cell cycle regulation,
           hypoxic responses, and antioxidant properties: Insight into the
           Development of Novel Radiosensitizing Strategies
    • Authors: Yoko Goto; Sho Kpyasu; Minoru Kobayashi; Hiroshi Harada
      Abstract: Publication date: Available online 22 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yoko Goto, Sho Kpyasu, Minoru Kobayashi, Hiroshi Harada
      Radiation therapy is one of the first-line treatments for many cancers, with no less than half of cancer patients receiving it in the US. Despite the development of innovative and high-precision radiation therapy strategies, many patients still experience local tumor recurrence after the treatment, at least in part, due to the existence of radioresistant cells in malignant tumor tissues. Among the various biological processes known to induce radioresistance, a post-translational protein modification, ubiquitination, has received marked attention in recent years. Ubiquitination, in which highly conserved ubiquitin polypeptides are covalently attached to their target proteins, has long been recognized as a system to tag unnecessary proteins for 26S proteasome-dependent proteolysis. However, accumulating lines of evidence recently revealed that it acts as a signal molecule in diverse biological processes as well, and its functional disorder was found to cause not only tumor development and various diseases but also tumor radioresistance. The present review summarizes the latest knowledge about how the cancer-related disorder of the ubiquitination systems induces the radioresistance of cancer cells by influencing intrinsic pathways, each of which potentially affects the radioresistance/radiosensitivity of cells, such as DNA damage responses, cell cycle regulation, hypoxic responses, and antioxidant properties. In addition, this review aims to provide insights into how we can exploit the disorders in order to develop novel radiosensitizing strategies.

      PubDate: 2017-07-25T15:27:57Z
      DOI: 10.1016/j.mrfmmm.2017.07.007
       
  • DNA Damage Levels in Electronics Workers in Southern China: A Micro-Whole
           Blood Comet Assay
    • Authors: Zhiqiang Zhao; Xiumei Xing; Xiaoyan Ou; Xinxia Liu; Ridong Zhou; Huimin Zhang; Linqing Yang; Zhixiong Zhuang; Xiaolin Su; Yao Lu; Jun Jiang; Yarui Yang; Dong Cui; Yun He
      Abstract: Publication date: Available online 22 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Zhiqiang Zhao, Xiumei Xing, Xiaoyan Ou, Xinxia Liu, Ridong Zhou, Huimin Zhang, Linqing Yang, Zhixiong Zhuang, Xiaolin Su, Yao Lu, Jun Jiang, Yarui Yang, Dong Cui, Yun He
      We evaluated DNA damage levels of different categories of workers exposed to hazards inside electronics factories in Southern China. To find out the most dangerous risk factor, a cross-sectional study was conducted on a total of 584 exposed subjects and 138 controls in an electronics factory in Southern China, where the electronics industry is prevalent. The exposed hazards included isopropanol (IPO), lead, noise, video display terminals (VDT), lead in a high-temperature (high-temp) environment, and IPO in a high-temp environment. DNA damage detection was performed by the micro-whole blood comet assay using peripheral blood. DNA damage levels were estimated by percent tail DNA (%T). Linear regression models were used to test DNA damage differences between exposed groups and control group with adjustments for potential confounding factors. The level of DNA damage was more significant in both lead in a high-temp and IPO in a high-temp environment groups than in that of the controls (p< 0.05). The differences remained significant after stratifying by smoking status (p< 0.05). There were no significant differences between groups exposed to IPO, lead, noise, VDT environment and controls. In conclusion, we identified potential risk factors for DNA damage to electronics workers. Special attention should be paid to workers exposed to IPO and lead in a high-temp environment.

      PubDate: 2017-07-25T15:27:57Z
      DOI: 10.1016/j.mrfmmm.2017.07.005
       
  • Balancing act: To be or not to be ubiquitylated
    • Authors: Ryotaro Nishi
      Abstract: Publication date: Available online 21 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ryotaro Nishi
      DNA double-strand breaks (DSBs) are one of the most deleterious DNA lesions. Appropriate repair of DSB either by homologous recombination or non-homologous end-joining is critical for maintaining genome stability and fitness. DSB repair cooperates with cellular signalling networks, namely DSB response (DDR), which plays pivotal roles in the choice of DSB repair pathway, orchestrating recruitment of DDR factors to site of damage, transcription suppression and cell cycle checkpoint activation. It has been revealed that these mechanisms are strictly regulated, in time and space, by complex and minute ubiquitylation-mediated reactions. Furthermore, balancing the ubiquitylation status of the DDR and DSB repair proteins by deubiquitylation, which is carried out by deubiquitylating enzymes (DUBs), is also found to be important. Recent findings have uncovered that DUBs are involved in various aspects of both DDR and DSB repair by counteracting non-proteolytic ubiquitylations in addition to protecting substrates from proteasomal degradation by removing proteolytic ubiquitylation. An advanced understanding of the detailed molecular mechanisms of the “balancing act” between ubiquitylation and deubiquitylation will provide novel therapeutic targets for diseases caused by dysfunction of DDR and DSB repair.

      PubDate: 2017-07-25T15:27:57Z
      DOI: 10.1016/j.mrfmmm.2017.07.006
       
  • Mutational signatures efficiently identify different mutational processes
           underlying cancers with similar somatic mutation spectra
    • Authors: Nan Zhou; Yuan Yuan; Xin Long; Chuanfang Wu; Jinku Bao
      Abstract: Publication date: Available online 19 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Nan Zhou, Yuan Yuan, Xin Long, Chuanfang Wu, Jinku Bao
      Compared to analyzing mutations with conventional spectra, deciphering mutational signatures provides much greater resolution of biological processes that generate somatic mutations during cancer development. Previous studies of bladder urothelial cancer (BLCA) and cervical squamous cell carcinoma (CESC) mutational signatures failed to uncover different mutational processes underlying the two cancers, which diminishes the capability of mutational signature to differentiate between the two cancers. In this study, we deciphered and compared the mutational signatures of BLCA and CESC. Four BLCA mutational signatures were deciphered from 37,098 somatic mutations of 130 exomes. Five CESC mutational signatures were deciphered from 44,206 somatic mutations of 194 exomes. Three BLCA mutational signatures were very similar to the three CESC signatures. These mutational signatures exhibited common endogenous mutational processes during BLCA and CESC development. The respective BLCA and CESC mutational signature 4 revealed the role of viral infection in both cancers. Noticeably, CESC mutational signature 4 is a novel one that has not been described in other studies. In summary, we have demonstrated the similarities and differences between BLCA and CESC by deciphering mutational signatures. This study will shed light on the use of mutational signatures to clarify the mechanisms of endogenous and exogenous carcinogens that cause somatic mutations in human cancers.

      PubDate: 2017-07-25T15:27:57Z
      DOI: 10.1016/j.mrfmmm.2017.07.004
       
  • Microhomology-Mediated End Joining: Good, Bad and Ugly
    • Authors: Ja-Hwan Seol; Eun Yong Shim; Sang Eun Lee
      Abstract: Publication date: Available online 16 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ja-Hwan Seol, Eun Yong Shim, Sang Eun Lee
      DNA double-strand breaks (DSBs) are induced by a variety of genotoxic agents, including ionizing radiation and chemotherapy drugs for treating cancers. The elimination of DSBs proceeds via distinctive error-free and error-prone pathways. Repair by homologous recombination (HR) is largely error-free and mediated by RAD51/BRCA2 gene products. Classical non-homologous end joining (C-NHEJ) requires the Ku heterodimer and can efficiently rejoin breaks, with occasional loss or gain of DNA information. Recently, evidence has unveiled another DNA end-joining mechanism that is independent of recombination factors and Ku proteins, termed alternative non-homologous end joining (A-NHEJ). While A-NHEJ-mediated repair does not require homology, in a subtype of A-NHEJ, DSB breaks are sealed by microhomology (MH)-mediated base-pairing of DNA single strands, followed by nucleolytic trimming of DNA flaps, DNA gap filling, and DNA ligation, yielding products that are always associated with DNA deletion. This highly error-prone DSB repair pathway is termed microhomology-mediated end joining (MMEJ). Dissecting the mechanisms of MMEJ is of great interest because of its potential to destabilize the genome through gene deletions and chromosomal rearrangements in cells deficient in canonical repair pathways, including HR and C-NHEJ. In addition, evidence now suggests that MMEJ plays a physiological role in normal cells.

      PubDate: 2017-07-19T15:09:59Z
      DOI: 10.1016/j.mrfmmm.2017.07.002
       
  • Ubiquitin-like modifications in the DNA damage response
    • Authors: Zhifeng Wang; Wei-Guo Zhu; Xingzhi Xu
      Abstract: Publication date: Available online 11 July 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Zhifeng Wang, Wei-Guo Zhu, Xingzhi Xu
      Genomic DNA is damaged at an extremely high frequency by both endogenous and environmental factors. An improper response to DNA damage can lead to genome instability, accelerate the aging process and ultimately cause various human diseases, including cancers and neurodegenerative disorders. The mechanisms that underlie the cellular DNA damage response (DDR) are complex and are regulated at many levels, including at the level of post-translational modification (PTM). Since the discovery of ubiquitin in 1975 and ubiquitylation as a form of PTM in the early 1980s, a number of ubiquitin-like modifiers (UBLs) have been identified, including small ubiquitin-like modifiers (SUMOs), neural precursor cell expressed, developmentally down-regulated 8 (NEDD8), interferon-stimulated gene 15 (ISG15), human leukocyte antigen (HLA)-F adjacent transcript 10 (FAT10), ubiquitin-fold modifier 1 (UFRM1), URM1 ubiquitin-related modifier-1 (URM1), autophagy-related protein 12 (ATG12), autophagy-related protein 8 (ATG8), fan ubiquitin-like protein 1 (FUB1) and histone mono-ubiquitylation 1 (HUB1). All of these modifiers have known roles in the cellular response to various forms of stress, and delineating their underlying molecular mechanisms and functions is fundamental in enhancing our understanding of human disease and longevity. To date, however, the molecular mechanisms and functions of these UBLs in the DDR remain largely unknown. This review summarizes the current status of PTMs by UBLs in the DDR and their implication in cancer diagnosis, therapy and drug discovery.

      PubDate: 2017-07-19T15:09:59Z
      DOI: 10.1016/j.mrfmmm.2017.07.001
       
  • Mutagenic potential of hypoxanthine in live human cells
    • Authors: Stephen DeVito; Jordan Woodrick; Linze Song; Rabindra Roy
      Abstract: Publication date: Available online 28 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Stephen DeVito, Jordan Woodrick, Linze Song, Rabindra Roy
      Hypoxanthine (Hx) is a major DNA lesion generated by deamination of adenine during chronic inflammatory conditions, which is an underlying cause of various diseases including cancer of colon, liver, pancreas, bladder and stomach. There is evidence that deamination of DNA bases induces mutations, but no study has directly linked Hx accumulation to mutagenesis and strand-specific mutations yet in human cells. Using a site-specific mutagenesis approach, we report the first direct evidence of mutation potential and pattern of Hx in live human cells. We investigated Hx-induced mutations in human nonmalignant HEK293 and cancer HCT116 cell lines and found that Hx is mutagenic in both HEK293 and HCT116 cell lines. There is a strand bias for Hx-mediated mutations in both the cell lines; the Hx in lagging strand is more mutagenic than in leading strand. There is also some difference in cell types regarding the strand bias for mutation types; HEK293 cells showed largely deletion (>80%) mutations in both leading and lagging strand and the rest were insertions and A:T→G:C transition mutations in leading and lagging strands, respectively, whereas in HCT116 cells we observed 60% A:T→G:C transition mutations in the leading strand and 100% deletions in the lagging strand. Overall, Hx is a highly mutagenic lesion capable of generating A:T→G:C transitions and large deletions with a significant variation in leading and lagging strands in human cells. In recent meta-analysis study A→G (T→C) mutations were found to be a prominent signature in a variety of cancers, including a majority types that are induced by inflammation. The deletions are known to be a major cause of copy-number variations or CNVs, which is a major underlying cause of many human diseases including mental illness, developmental disorders and cancer. Thus, Hx, a major DNA lesion induced by different deamination mechanisms, has potential to initiate inflammation-driven carcinogenesis in addition to various human pathophysiological consequences.

      PubDate: 2017-07-01T13:47:51Z
      DOI: 10.1016/j.mrfmmm.2017.06.005
       
  • So similar yet so different: the two ends of a double strand break
    • Authors: Keun P. Kim; Ekaterina V. Mirkin
      Abstract: Publication date: Available online 27 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Keun P. Kim, Ekaterina V. Mirkin
      Homologous recombination (HR) is essential for ensuring proper segregation of chromosomes in the first round of meiotic division. HR is also crucial for preserving genomic integrity of somatic cells due to its ability to rescue collapsed replication forks and eliminate deleterious DNA lesions, such as double-strand breaks (DSBs), interstrand crosslinks, and single-strand DNA gaps. Here, we review the early steps of HR (homology search and strand exchange), focusing on the roles of the two ends of a DSB. A detailed overview of the basic HR machinery and its mechanism for template selection and capture of duplex DNA via strand exchange is provided. Roles of proteins involved in these steps are discussed in both mitotic and meiotic HR. Central to this review is the hypothesis, which suggests that in meiosis, HR begins with a symmetrical DSB, but the symmetry is quickly lost with the two ends assuming different roles; it argues that this disparity of the two ends is essential for regulation of HR in meiosis and successful production of haploid gametes. We also propose a possible evolutionary reason for the asymmetry of the ends in HR.

      PubDate: 2017-07-01T13:47:51Z
      DOI: 10.1016/j.mrfmmm.2017.06.007
       
  • Enhanced DNA double-strand break repair of microbeam targeted A549 lung
           carcinoma cells by adjacent WI38 normal lung fibroblast cells via
           bi-directional signaling
    • Authors: Alisa Kobayashi; Tengku Ahbrizal Farizal Tengku Ahmad; Narongchai Autsavapromporn; Masakazu Oikawa; Shino Homma-Takeda; Yoshiya Furusawa; Jun Wang; Teruaki Konishi
      Abstract: Publication date: Available online 23 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Alisa Kobayashi, Tengku Ahbrizal Farizal Tengku Ahmad, Narongchai Autsavapromporn, Masakazu Oikawa, Shino Homma-Takeda, Yoshiya Furusawa, Jun Wang, Teruaki Konishi
      Understanding the mechanisms underlying the radiation-induced bystander effect (RIBE) and bi-directional signaling between irradiated carcinoma cells and their surrounding non-irradiated normal cells is relevant to cancer radiotherapy. The present study investigated propagation of RIBE signals between human lung carcinoma A549 cells and normal lung fibroblast WI38 cells in bystander cells, either directly or indirectly contacting irradiated A549 cells. We prepared A549-GFP/WI38 co-cultures and A549-GFP/A549 co-cultures, in which A549-GFP cells stably expressing H2BGFP were co-cultured with either A549 cells or WI38 cells, respectively. Using the SPICE-NIRS microbeam, only the A549-GFP cells were irradiated with 500 protons per cell. The level of γ-H2AX, a marker for DNA double-strand breaks (DSB), was subsequently measured for up to 24h post-irradiation in three categories of cells: (1) “targeted”/irradiated A549-GFP cells; (2) “neighboring”/non-irradiated cells directly contacting the “targeted” cells; and (3) “distant”/non-irradiated cells, which were not in direct contact with the “targeted” cells. We found that DSB repair in targeted A549-GFP cells was enhanced by co-cultured WI38 cells. The bystander response in A549-GFP/A549 cell co-cultures, as marked by γ-H2AX levels at 8h post-irradiation, showed a decrease to non-irradiated control level when approaching 24h, while the neighboring/distant bystander WI38 cells in A549-GFP/WI38 co-cultures was maintained at a similar level until 24h post-irradiation. Surprisingly, distant A549-GFP cells in A549-GFP/WI38 co-cultures showed time dependency similar to bystander WI38 cells, but not to distant cells in A549-GFP/A549 co-cultures. These observations indicate that γ-H2AX was induced in WI38 cells as a result of RIBE. WI38 cells were not only involved in rescue of targeted A549, but also in the modification of RIBE against distant A549-GFP cells. The present results demonstrate that radiation-induced bi-directional signaling had extended a profound influence on cellular sensitivity to radiation as well as the sensitivity to RIBE.

      PubDate: 2017-07-01T13:47:51Z
      DOI: 10.1016/j.mrfmmm.2017.06.006
       
  • Regulation of DNA damage tolerance in mammalian cells by
           post-translational modifications of PCNA
    • Authors: Rie Kanao; Chikahide Masutani
      Abstract: Publication date: Available online 21 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Rie Kanao, Chikahide Masutani
      DNA damage tolerance pathways, which include translesion DNA synthesis (TLS) and template switching, are crucial for prevention of DNA replication arrest and maintenance of genomic stability. However, these pathways utilize error-prone DNA polymerases or template exchange between sister DNA strands, and consequently have the potential to induce mutations or chromosomal rearrangements. Post-translational modifications of proliferating cell nuclear antigen (PCNA) play important roles in controlling these pathways. For example, TLS is mediated by mono-ubiquitination of PCNA at lysine 164, for which RAD6–RAD18 is the primary E2–E3 complex. Elaborate protein–protein interactions between mono-ubiquitinated PCNA and Y-family DNA polymerases constitute the core of the TLS regulatory system, and enhancers of PCNA mono-ubiquitination and de-ubiquitinating enzymes finely regulate TLS and suppress TLS-mediated mutagenesis. The template switching pathway is promoted by K63-linked poly-ubiquitination of PCNA at lysine 164. Poly-ubiquitination is achieved by a coupled reaction mediated by two sets of E2–E3 complexes, RAD6–RAD18 and MMS2–UBC13–HTLF/SHPRH. In addition to these mono- and poly-ubiquitinations, simultaneous mono-ubiquitinations on multiple units of the PCNA homotrimeric ring promote an unidentified damage tolerance mechanism that remains to be fully characterized. Furthermore, SUMOylation of PCNA in mammalian cells can negatively regulate recombination. Other modifications, including ISGylation, acetylation, methylation, or phosphorylation, may also play roles in DNA damage tolerance and control of genomic stability.

      PubDate: 2017-06-22T13:14:08Z
       
  • Mut Res special section “Protein modifications in DNA repair and
           cancer”
    • Authors: Minoru Takata
      Abstract: Publication date: Available online 15 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Minoru Takata


      PubDate: 2017-06-16T12:54:55Z
      DOI: 10.1016/j.mrfmmm.2017.06.003
       
  • Editorial
    • Authors: Minoru Takata
      Abstract: Publication date: Available online 10 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Minoru Takata


      PubDate: 2017-06-12T12:43:48Z
      DOI: 10.1016/j.mrfmmm.2017.06.001
       
  • Variable spontaneous mutation rate in clinical strains of
           multidrug-resistant Acinetobacter baumannii and differentially expressed
           proteins in a hypermutator strain
    • Authors: Morteza Karami-Zarandi; Masoumeh Douraghi; Behrouz Vaziri; Habibeh Adibhesami; Mohammad Rahbar; Mehdi Yaseri
      Abstract: Publication date: Available online 8 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Morteza Karami-Zarandi, Masoumeh Douraghi, Behrouz Vaziri, Habibeh Adibhesami, Mohammad Rahbar, Mehdi Yaseri
      Background The emergence of multidrug resistant Acinetobacter baumannii within hospitals poses a significant threat to patients. The inherent rate of mutation of these strains has not been described nor has the mechanism by which drug resistance arises. Methods Here, we determined the spontaneous mutation rates in 93 clinical strains of A. baumannii using fluctuation analysis. To rule out the clonal relatedness of hypermutator strains, pulsed-field gel electrophoresis (PFGE) was conducted. Using a combination of two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry, the differentially expressed proteins of a hypermutator and a reference strain were identified. Results The spontaneous mutation rate of multi-drug resistant A. baumannii strains varied broadly from 0 to 2.1×10−6 mutation per cell division. The mutation rate in three multidrug resistant A. baumannii (MDR-AB) strains was found to be 1.63×10−6 (95% confidence interval (CI): 1×10−6–2×10−6), 2.1×10−6 (95% CI: 2×10−6 − 3×10−6), and 1.78×10−8 (95% CI: 9.29×10−9 2.95×10−8), consistent with a hypermutator phenotype. This rate is approximately 1000-fold higher than the average mutation rate in other MDR-ABs. PFGE of the three hypermutator strains indicate that they belong to distinct clones. Proteomic analysis of one hypermutator strain revealed 31 differentially expressed proteins including three with sizes of 51.2, 20.9, and 11.9kDa, which corresponded to a serine protease, a polyisoprenoid-binding protein, and the peptidoglycan binding protein, LysM. The serine protease was expressed only in the hypermutator strain, whereas the polyisoprenoid-binding protein and the peptidoglycan binding protein LysM were down-regulated 1.6 and 3-fold, respectively, in the hypermutators strain. Conclusion Hypermutator A. baumannii strains occur with a low, but appreciable frequency among clinical multi-drug resistant isolates. The presence of hypermutator clinical isolates raises concerns that they may contribute to the failure of antibiotic treatment in infected patients and confound the interpretation of in vitro antibiotic susceptibility testing. The differentially expressed proteins involved in biofilm suppression and oxidative stress response, may represent adaptations derived from the hypermutator phenotype, a hypothesis that needs further testing.

      PubDate: 2017-06-12T12:43:48Z
      DOI: 10.1016/j.mrfmmm.2017.06.002
       
  • Eukaryotic DNA damage responses: Homologous recombination factors and
           ubiquitin modification
    • Authors: Nam Soo Lee; Soomi Kim; Yong Woo Jung; Hongtae Kim
      Abstract: Publication date: Available online 6 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Nam Soo Lee, Soomi Kim, Yong Woo Jung, Hongtae Kim
      To prevent genomic instability disorders, cells have developed a DNA damage response. The response involves various proteins that sense damaged DNA, transduce damage signals, and effect DNA repair. In addition, ubiquitin modifications modulate the signaling pathway depending on cellular context. Among various types of DNA damage, double-stranded breaks are highly toxic to genomic integrity. Homologous recombination (HR) repair is an essential mechanism that fixes DNA damage because of its high level of accuracy. Although factors in the repair pathway are well established, pinpointing the exact mechanisms of repair and devising therapeutic applications requires more studies. Moreover, essential functions of ubiquitin modification in the DNA damage signaling pathway have emerged. In this review, to explore the eukaryotic DNA damage response, we will mention the functions of main factors in the HR repair pathway and ubiquitin modification.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.04.003
       
  • The functional roles of PML nuclear bodies in genome maintenance
    • Authors: Hae Ryung Chang; Anudari Munkhjargal; Myung-Jin Kim; Seon Young Park; Eunyoung Jung; Jae-Ha Ryu; Young Yang; Jong-Seok Lim; Yonghwan Kim
      Abstract: Publication date: Available online 5 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Hae Ryung Chang, Anudari Munkhjargal, Myung-Jin Kim, Seon Young Park, Eunyoung Jung, Jae-Ha Ryu, Young Yang, Jong-Seok Lim, Yonghwan Kim
      In the nucleus, there are several membraneless structures called nuclear bodies. Among them, promyelocytic leukemia nuclear bodies (PML-NBs) are involved in multiple genome maintenance pathways including the DNA damage response, DNA repair, telomere homeostasis, and p53-associated apoptosis. In response to DNA damage, PML-NBs are coalesced and divided by a fission mechanism, thus increasing their number. PML-NBs also play a role in repairing DNA double-strand breaks (DSBs) by homologous recombination (HR). Clinically, the dominant negative PML-RARα fusion protein expressed in acute promyelocytic leukemia (APL) inhibits the transactivation of downstream factors and disrupts PML function, revealing the tumor suppressor role of PML-NBs. All-trans retinoic acid and arsenic trioxide treatment has been implemented for promyelocytic leukemia to target the PML-RARα fusion protein. PML-NBs are associated with various factors implicated in genome maintenance, and are found at the sites of DNA damage. Their interaction with proteins such as p53 indicates that PML-NBs may play a significant role in apoptosis and cancer. Decades of research have revealed the importance of PML-NBs in diverse cellular pathways, yet the underlying molecular mechanisms and exact functions of PML-NBs remain elusive. In this review, PML protein modifications and the functional relevance of PML-NB and its associated factors in genome maintenance will be discussed.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.05.002
       
  • Activation of the FA pathway mediated by phosphorylation and
           ubiquitination
    • Authors: Masamichi Ishiai; Koichi Sato; Junya Tomida; Hiroyuki Kitao; Hitoshi Kurumizaka; Minoru Takata
      Abstract: Publication date: Available online 5 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Masamichi Ishiai, Koichi Sato, Junya Tomida, Hiroyuki Kitao, Hitoshi Kurumizaka, Minoru Takata
      Fanconi anemia (FA) is a devastating hereditary condition that impacts genome integrity, leading to clinical features such as skeletal and visceral organ malformations, attrition of bone marrow stem cells, and carcinogenesis. At least 21 proteins, when absent or defective, have been implicated in this disorder, and they together constitute the FA pathway, which functions in detection and repair of, and tolerance to, endogenous DNA damage. The damage primarily handled by the FA pathway has been assumed to be related to DNA interstrand crosslinks (ICLs). The FA pathway is activated upon ICL damage, and a hallmark of this activation is the mono-ubiquitination events of the key FANCD2-FANCI protein complex. Recent data have revealed unexpectedly complex details in the regulation of FA pathway activation by ICLs. In this short review, we summarize the knowledge accumulated over the years regarding how the FA pathway is activated via protein modifications.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.05.003
       
  • Targeted sequencing identifies novel variants involved in Autosomal
           Recessive Hereditary Hearing Loss in Qatari families
    • Authors: Moza K. Alkowari; Diego Vozzi; Shruti Bhagat; Navaneethakrishnan Krishnamoothy; Anna Morgan; Yousra Hayder; Barathy Logendra; Nehal Najjar; Ilaria Gandin; Paolo Gasparini; Ramin Badii; Giorgia Girotto; Khalid Abdulhadi
      Abstract: Publication date: Available online 4 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Moza K. Alkowari, Diego Vozzi, Shruti Bhagat, Navaneethakrishnan Krishnamoothy, Anna Morgan, Yousra Hayder, Barathy Logendra, Nehal Najjar, Ilaria Gandin, Paolo Gasparini, Ramin Badii, Giorgia Girotto, Khalid Abdulhadi
      Hereditary hearing loss (HHL) is characterized by a very high genetic heterogeneity. In the Qatari population the role of GJB2, the worldwide HHL major player, seems to be quite limited compared to Caucasian populations. In this study we analysed 18 Qatari families affected by non-syndromic hearing loss using a targeted sequencing approach that allowed us to analyse 81 genes simultaneously. Thanks to this approach, 50% of these families (9 out of 18) resulted positive for the presence of likely causative alleles in 6 different genes: CDH23, MYO6, GJB6, OTOF, TMC1 and OTOA. In particular, 4 novel alleles were detected while the remaining ones were already described to be associated to HHL in other ethnic groups. Molecular modelling has been used to further investigate the role of novel alleles identified in CDH23 and TMC1 genes demonstrating their crucial role in Ca2+ binding and therefore possible functional role in proteins. Present study showed that an accurate molecular diagnosis based on next generation sequencing technologies might largely improve molecular diagnostics outcome leading to benefits for both genetic counseling and definition of recurrence risk.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.05.001
       
  • Eukaryotic DNA replication: Orchestrated action of Multi-subunit protein
           complexes
    • Authors: Sukhyun Kang; Mi-Sun Kang; Eunjin Ryu; Kyungjae Myung
      Abstract: Publication date: Available online 1 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Sukhyun Kang, Mi-Sun Kang, Eunjin Ryu, Kyungjae Myung
      Genome duplication is an essential process to preserve genetic information between generations. The eukaryotic cell cycle is composed of functionally distinct phases: G1, S, G2, and M. One of the key replicative proteins that participate at every stage of DNA replication is the Mcm2-7 complex, a replicative helicase. In the G1 phase, inactive Mcm2-7 complexes are loaded on the replication origins by replication-initiator proteins, ORC and Cdc6. Two kinases, S-CDK and DDK, convert the inactive origin-loaded Mcm2-7 complex to an active helicase, the CMG complex in the S phase. The activated CMG complex begins DNA unwinding and recruits enzymes essential for DNA synthesis to assemble a replisome at the replication fork. After completion of DNA synthesis, the inactive CMG complex on the replicated DNA is removed from chromatin to terminate DNA replication. In this review, we will discuss the structure, function, and regulation of the molecular machines involved in each step of DNA replication.

      PubDate: 2017-05-02T09:29:20Z
      DOI: 10.1016/j.mrfmmm.2017.04.002
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 797–799


      PubDate: 2017-05-02T09:29:20Z
       
  • 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
       
  • INTERNATIONAL ORGANIZATIONS, RISK ASSESSMENT AND RESEARCH–WHY, WHAT
           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
       
  • TITLE PAGE (EDI BOARD)
    • 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
       
  • TITLE PAGE (EDI BOARD)
    • 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
       
 
 
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