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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  [3089 journals]
  • Identification of intronic-splice site mutations in GATA4 gene in Indian
           patients with congenital heart disease
    • Authors: Divya Bose; Vaigundan D.; Mitesh Shetty; Krishnappa J.; A.V.M. Kutty
      Pages: 26 - 34
      Abstract: Publication date: October 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 803–805
      Author(s): Divya Bose, Vaigundan D., Mitesh Shetty, Krishnappa J., A.V.M. Kutty
      Congenital Heart Disease (CHD) is the most common birth defect among congenital anomalies that arise before birth. GATA4 transcription factor plays an important role in foetal heart development. Mutational analysis of GATA4 gene in CHD patients revealed five known heterozygous mutations (p.T355S, p.S377G, p.V380M, p.P394T and p.D425N) identified in exons 5 and 6 regions and fifteen intronic variants in the non-coding regions (g.76885T>C/Y,g.76937G>S, g.78343G>R, g.83073T>Y, g.83271C>A/M, g.83318G>K, g.83415G>R, g.83502A>C/M, g.84991G>R, g.85294C>Y, g.85342C>T/Y, g.86268A>R, g.87409G>A/R, g.87725T>Y, g.87813A>T/W). In silico analysis of these intronic variants identified two potential branch point mutations (g.83271C>A/M, g.86268A>R) and predicted effects of these on intronic splice sites as enhancer and silencer motifs. This study attempts to correlate the pattern of intronic variants of GATA4 gene which might provide new insights to unravel the possible molecular etiology of CHD.

      PubDate: 2017-08-24T17:24:33Z
      DOI: 10.1016/j.mrfmmm.2017.08.001
      Issue No: Vol. 803-805 (2017)
  • Corrigendum to “Estimation of the minimum mRNA splicing error rate in
           vertebrates” [Mutat Res. 2016;784:34-38]
    • Authors: A. Skandalis
      First page: 46
      Abstract: Publication date: August 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 800–802
      Author(s): A. Skandalis

      PubDate: 2017-09-20T17:13:09Z
      DOI: 10.1016/j.mrfmmm.2017.07.010
      Issue No: Vol. 800-802 (2017)
  • Strategies for identification of mutations induced by carbon-ion beam
           irradiation in Arabidopsis thaliana by whole genome re-sequencing
    • Authors: Yan Shanwei; Luo Lixia Tao Cui Xia Chen Jiangyan Yang
      Abstract: Publication date: Available online 9 December 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yan Du, Shanwei Luo, Lixia Yu, Tao Cui, Xia Chen, Jiangyan Yang, Xin Li, Wenjian Li, Jufang Wang, Libin Zhou
      Heavy-ion beam irradiation is a powerful physical mutagen that has been used to create numerous mutant materials in plants. These materials are an essential resource for functional genomics research in the post-genome era. The advent of next-generation sequencing (NGS) technology has promoted the study of functional genomics and molecular breeding. A wealth of information can be gathered from whole genome re-sequencing; however, understanding the molecular mutation profile at genome wide, as well as identifying causal genes for a given phenotype are big challenging issues for researchers. The huge outputs created by NGS make it difficult to capture key information. It is worthy to explore an effective and efficient data-sieving strategy for mutation scanning at whole genome scale. Re-sequencing data from one laboratory wild type (Columbia) and eleven M3 Arabidopsis thaliana lines derived from carbon-ion beam irradiation were used in present study. Both the number and different combinations of samples used for analysis affected the sieving results. The result indicated that using six samples was sufficient to filter out the shared mutation (background interference) sites as well as to identify the true mutation sites in the whole genome. The final number of candidate mutation sites could be further narrowed down by combining traditional rough map-based cloning. Our results demonstrated the feasibility of a parallel sequencing analysis as an efficient tool for the identification of mutations induced by carbon-ion beam irradiation. For the first time, we presented different analysis strategies for handling massive parallel sequencing data sets to detect the mutations induced by carbon-ion beam irradiation in Arabidopsis thaliana with low false-positive rate, as well as to identify the causative nucleotide changes responsible for a mutant phenotype.

      PubDate: 2017-12-12T02:22:03Z
    • Abstract: Publication date: December 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 806

      PubDate: 2017-12-08T02:08:12Z
  • Association of H3K79 monomethylation (an epigenetic signature) with
           arsenic-induced skin lesions
    • Authors: Pritha Bhattacharjee; Somnath Paul; Sandip Bhattacharjee; Ashok K. Giri; Pritha Bhattacharjee
      Abstract: Publication date: Available online 14 November 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Pritha Bhattacharjee, Somnath Paul, Sandip Bhattacharjee, Ashok K. Giri, Pritha Bhattacharjee
      Arsenic, a non mutagenic carcinogen, poses a profound health risk upon prolonged exposure. The objective of the study was to analyze the post-translational modifications of the major histone H3 and the associated molecular crosstalk to identify the epigenetic signature of arsenic susceptibility. Herein, we identified significant upregulation of H3K79me1, in individuals with arsenic-induced skin lesion (WSL), and H3K79me1 was found to be regulated by the upstream methyltransferase DOT1L. Moreover, the downstream target molecule 53BP1, a tumor suppressor protein that has a docking preference for H3K79me1 at a site of a double-strand break (DSB), was downregulated, indicating greater DNA damage in the WSL group. Western blot data confirmed higher levels of γH2AX, a known marker of DSBs, in group WSL. In vitro dose–response analysis also confirmed the association of the H3K79me1 signature with arsenic toxicity. Taken together, our findings revealed that H3K79me1 and DOT1L could be a novel epigenetic signature of the arsenic-exposed WSL group.

      PubDate: 2017-11-16T12:14:26Z
      DOI: 10.1016/j.mrfmmm.2017.11.001
  • Molecular criteria for mutagenesis by DNA methylation: some computational
    • Authors: Tejeshwori Salam; S. Premila Devi; R.H. Duncan Lyngdoh
      Abstract: Publication date: Available online 10 November 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Tejeshwori Salam, S. Premila Devi, R.H. Duncan Lyngdoh
      Alkylating agents and N-nitroso compounds are well-known mutagens and carcinogens which act by alkylating DNA at the nucleobase moieties. Criteria for mutagenicity through DNA alkylation include (a) absence of the Watson-Crick (N1-guanine and N3-thymine) protons, (b) rotation of the alkyl group away from the H-bonding zone, (c) configuration of the alkylated base pair close to the Watson-Crick type. This computational study brings together these three molecular criteria for the first time. Three methylated DNA bases − N7-methylguanine, O6-methylguanine and O4-methylthymine − are studied using computational chemical methods. Watson-Crick proton loss is predicted more feasible for the mutagenic O6-methylguanine and O4-methylthymine than for the non-mutagenic N7-methylguanine in agreement with the observed trend for pKa values. Attainment of a conformer conducive to mutagenesis is more feasible for O6-methylguanine than for O4-methylthymine, though the latter is more mutagenic. These methylated bases yield 9 H-bonded pairs with normal DNA bases. At biological pH, O6-methylguanine and O4-methylthymine would yield stable mutagenic pairs having Watson-Crick type configuration by H-bonded pairing with thymine and guanine respectively, while N7-methylguanine would yield a non-mutagenic pair with cytosine. The three criteria thus well differentiate the non-mutagenic N7-methylguanine from the mutagenic O6-methylguanine and O4-methylthymine in good accord with experimental observations.

      PubDate: 2017-11-16T12:14:26Z
      DOI: 10.1016/j.mrfmmm.2017.10.004
  • Biological effects of carbon ion beams with various LETs on budding yeast
           Saccharomyces cerevisiae
    • Authors: Youichirou Matuo; Yoshinobu Izumi; Yoshiya Furusawa; Kikuo Shimizu
      Abstract: Publication date: Available online 7 November 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Youichirou Matuo, Yoshinobu Izumi, Yoshiya Furusawa, Kikuo Shimizu
      It has been established that irradiation with higher linear energy transfer (LET) increases lethality and mutagenicity more than that with lower LET. However, the characteristics specific to carbon ion beam have not yet been elucidated. Yeast cells were irradiated with carbon ions with an LET of 13 or 50 keV/μm, and cell survival and mutation frequency were analyzed. The results, combined with our previous findings for ions with an LET of 107 keV/μm, demonstrated that, in conjunction with an increase in LET, cell survival decreased, while mutation frequency increased. This indicates that a carbon ion beam with a higher LET is more mutagenic than one with a lower LET.

      PubDate: 2017-11-09T11:45:04Z
      DOI: 10.1016/j.mrfmmm.2017.10.003
  • DNA replication stress drives fragile site instability
    • Authors: Michal Irony-Tur Sinai; Batsheva Kerem
      Abstract: Publication date: Available online 18 October 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Michal Irony-Tur Sinai, Batsheva Kerem
      DNA replication stress is one of the early drivers enabling the ongoing acquisition of genetic changes arising during tumorigenesis. As such, it is a feature of most pre-malignant and malignant cells. In this review article, we focus on the early events initiating DNA replication stress and the preferential sensitivity of common fragile sites (CFSs) to this stress. CFSs are specific genomic regions within the normal chromosomal structure, which appear as gaps and breaks in the metaphase chromosomes of cells grown under mild replication stress conditions. The main characteristics predisposing CFSs to instability include late replication timing, delayed replication completion, failure to activate additional origins, origin paucity along large genomic regions, collision between replication and transcription complexes along large genes, and the presence of AT-dinucleotide rich sequences. The contribution of these features to instability at CFSs during early cancer development is discussed.

      PubDate: 2017-10-26T10:54:07Z
      DOI: 10.1016/j.mrfmmm.2017.10.002
  • Replication stress in hematopoietic stem cells in mouse and man
    • Authors: Johanna Flach; Michael Milyavsky
      Abstract: Publication date: Available online 18 October 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Johanna Flach, Michael Milyavsky
      Life-long blood regeneration relies on a rare population of self-renewing hematopoietic stem cells (HSCs). These cells’ nearly unlimited self-renewal potential and lifetime persistence in the body signifies the need for tight control of their genome integrity. Their quiescent state, tightly linked with low metabolic activity, is one of the main strategies employed by HSCs to preserve an intact genome. On the other hand, HSCs need to be able to quickly respond to increased blood demands and rapidly increase their cellular output in order to fight infection-associated inflammation or extensive blood loss. This increase in proliferation rate, however, comes at the price of exposing HSCs to DNA damage inevitably associated with the process of DNA replication. Any interference with normal replication fork progression leads to a specialized molecular response termed replication stress (RS). Importantly, increased levels of RS are a hallmark feature of aged HSCs, where an accumulating body of evidence points to causative relationships between RS and the aging-associated impairment of the blood system’s functional capacity. In this review, we present an overview of RS in HSCs focusing on its causes and consequences for the blood system of mice and men.

      PubDate: 2017-10-26T10:54:07Z
      DOI: 10.1016/j.mrfmmm.2017.10.001
    • Abstract: Publication date: October 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 803–805

      PubDate: 2017-10-03T06:57:29Z
  • Efficient repair of DNA double strand breaks in individuals from high
           level natural radiation areas of Kerala coast, south-west India
    • Authors: Vinay Jain; Divyalakshmi Saini; P.R. Vivek Kumar; G. Jaikrishan; Birajalaxmi Das
      Abstract: Publication date: Available online 20 September 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Vinay Jain, Divyalakshmi Saini, P.R. Vivek Kumar, G. Jaikrishan, Birajalaxmi Das
      High level natural radiation areas (HLNRA) of Kerala coastal strip (55km long and 0.5km wide) in southwest India exhibit wide variations in the level of background dose (< 1.0 to 45.0mGy/year) due to thorium deposits in the beach sand. The areas with ≤1.5mGy/year are considered as normal level natural radiation area (NLNRA), whereas areas with >1.5mGy/year are HLNRA. Individuals belonging to HLNRA were stratified into two groups, Low dose group (LDG: 1.51–5.0mGy/year) and high dose group (HDG: >5.0mGy/year). The mean annual dose received by the individuals from NLNRA, LDG and HDG was 1.3±0.1, 2.7±0.9 and 9.4±2.3mGy/year, respectively. Induction and repair of DNA double strand breaks (DSBs) in terms of gamma-H2AX positive cells were analysed in peripheral blood mononuclear cells (PBMCs) using flow cytometry. Induction of DSBs was studied at low (0.25Gy) and high challenge doses (1.0 and 2.0Gy) of gamma radiation in 78 individuals {NLNRA, N=23; HLNRA (LDG, N=21 and HDG, N=34)}. Repair kinetics of DSBs were evaluated in PBMCs of 30 individuals belonging to NLNRA (N=8), LDG (N=7) and HDG (N=15) at low (0.25Gy) and high doses (2.0Gy) of gamma radiation. Transcriptional profile of DNA damage response (DDR) and DSB repair genes involved in non-homologous end joining (NHEJ) and homologous recombination repair (HRR) pathways was analysed after a challenge dose of 2.0Gy in PBMCs of NLNRA (N=10) and HDG, HLNRA (N=10) group. Our results revealed significantly lower induction and efficient repair of DSBs in HLNRA groups as compared to NLNRA. Transcription profile of DCLRE1C, XRCC4, NBS1 and CDK2 showed significant up-regulation (p≤0.05) in HDG at a challenge dose of 2.0Gy indicating active involvement of DDR and DSB repair pathways. In conclusion, lower induction and efficient repair of DNA DSBs in HLNRA groups is suggestive of an in vivo radio-adaptive response due to priming effect of chronic low dose radiation prevailing in this area.

      PubDate: 2017-09-20T17:13:09Z
      DOI: 10.1016/j.mrfmmm.2017.09.003
  • p.Val19Glyfs*21 and p.Leu228* variants in the survival of motor neuron 1
           trigger nonsense-mediated mRNA decay causing the SMN1 PTC+ transcripts
    • Authors: Yu-jin Qu; Lin Ge; Jin-li Bai; Yan-yan Cao; Yu-wei Jin; Hong Wang; Lan Yang; Fang Song
      Abstract: Publication date: Available online 15 September 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yu-jin Qu, Lin Ge, Jin-li Bai, Yan-yan Cao, Yu-wei Jin, Hong Wang, Lan Yang, Fang Song
      Spinal Muscular Atrophy (SMA) results from loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene. Our previous research showed that 40% of variants were nonsense or frameshift variants and SMN1 mRNA levels in the patients carrying these variants were significantly decreased. Here we selected one rare variant (p.Val19Glyfs*21) and one common variant (p.Leu228*) to explore the degradation mechanism of mutant transcripts. The levels of full-length (FL)-SMN1 transcripts and SMN protein in the cell lines from the patients with these variants were both significantly reduced (p<0.01). Treatment with two translation inhibitors (puromycin and Cycloheximide (CHX)) markedly increased the levels of FL-SMN1 transcripts with premature translation termination codons (PTCs) (p<0.01) and showed time-dependent (10h>5.5h) but not dose-dependent effects. Moreover, the knockdown of UPF1, a key factor in nonsense-mediated mRNA decay (NMD) by lentivirus, led to a 3.08-fold increase (p<0.01) in FL-SMN1 transcript levels in patient fibroblasts. Our research provides evidence that these two PTC-generating variants (p.Val19Glyfs*21 and p.Leu228*) can trigger NMD, causing rapid degradation of SMN1 transcripts thereby resulting in SMN protein deficiency. These two variants are highly pathogenic and are associated with more severe SMA phenotypes. Varying NMD efficiency after treatment with puromycin and CHX in different cell types was also observed.

      PubDate: 2017-09-20T17:13:09Z
      DOI: 10.1016/j.mrfmmm.2017.09.005
  • Beyond interstrand crosslinks repair: contribution of FANCD2 and other
           Fanconi Anemia proteins to the replication of DNA
    • Authors: Maria B. Federico; Paola Campodónico; Natalia S. Paviolo; Vanesa Gottifredi
      Abstract: Publication date: Available online 14 September 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Maria B. Federico, Paola Campodónico, Natalia S. Paviolo, Vanesa Gottifredi
      Biallelic mutations of FANCD2 and other components of the Fanconi Anemia (FA) pathway cause a disease characterized by bone marrow failure, cancer predisposition and a striking sensitivity to agents that induce crosslinks between the two complementary DNA strands (inter-strand crosslinks-ICL). Such genotoxins were used to characterize the contribution of the FA pathway to the genomic stability of cells, thus unravelling the biological relevance of ICL repair in the context of the disease. Notwithstanding this, whether the defect in ICL repair as the sole trigger for the multiple physiological alterations observed in FA patients is still under investigation. Remarkably, ICL-independent functions of FANCD2 and other components of the FA pathway were recently reported. FANCD2 contributes to the processing of very challenging double strand ends (DSEs: one ended DSBs created during DNA replication). Other ICL-independent functions of FANCD2 include prevention of DNA breakage at stalled replication forks and facilitation of chromosome segregation at the end of M phase. The current understanding of replication-associated functions of FANCD2 and its relevance for the survival of genomically stable cells is herein discussed.

      PubDate: 2017-09-20T17:13:09Z
      DOI: 10.1016/j.mrfmmm.2017.09.004
    • Abstract: Publication date: August 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 800–802

      PubDate: 2017-09-20T17:13:09Z
  • Integration of the TGx-28.65 genomic biomarker with the flow cytometry
           micronucleus test to assess the genotoxicity of disperse orange and
           1,2,4-benzenetriol in human TK6 cells
    • Authors: Julie K. Buick; Andrew Williams; Byron Kuo; John W. Wills; Carol D. Swartz; Leslie Recio; Heng-Hong Li; Albert J. Fornace; Jiri Aubrecht; Carole L. Yauk
      Abstract: Publication date: Available online 13 September 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Julie K. Buick, Andrew Williams, Byron Kuo, John W. Wills, Carol D. Swartz, Leslie Recio, Heng-Hong Li, Albert J. Fornace, Jiri Aubrecht, Carole L. Yauk
      In vitro gene expression signatures to predict toxicological responses can provide mechanistic context for regulatory testing. We previously developed the TGx-28.65 genomic biomarker from a database of gene expression profiles derived from human TK6 cells exposed to 28 well-known compounds. The biomarker comprises 65 genes that can classify chemicals as DNA damaging or non-DNA damaging. In this study, we applied the TGx-28.65 genomic biomarker in parallel with the in vitro micronucleus (MN) assay to determine if two chemicals of regulatory interest at Health Canada, disperse orange (DO: the orange azo dye 3-[[4-[(4-Nitrophenyl)azo]phenyl] benzylamino]propanenitrile) and 1,2,4-benzenetriol (BT: a metabolite of benzene) are genotoxic or non-genotoxic. Both chemicals caused dose-dependent declines in relative survival and increases in apoptosis. A strong significant increase in MN induction was observed for all concentrations of BT; the top two concentrations of DO also caused a statistically significant increase in MN, but these increases were <2-fold above controls. TGx-28.65 analysis classified BT as genotoxic at all three concentrations and DO as genotoxic at the mid and high concentrations. Thus, although DO only induced a small increase in MN, this response was sufficient to induce a cellular DNA damage response. However, benchmark dose modeling confirmed that BT is much more potent than DO. The results strongly suggest that follow-up work is required to assess whether DO and BT are also genotoxic in vivo. This is particularly important for DO, which may require metabolic activation by bacterial gut flora to fully induce its genotoxic potential. Our previously published data and this proof of concept study suggest that the TGx-28.65 genomic biomarker has the potential to add significant value to existing approaches used to assess genotoxicity.

      PubDate: 2017-09-14T13:02:49Z
      DOI: 10.1016/j.mrfmmm.2017.09.002
  • Effect of Modeled Microgravity on UV-C-induced Interplant Communication of
           Arabidopsis thaliana
    • Authors: Ting Wang; Wei Xu; Huasheng Li; Chenguang Deng; Hui Zhao; Yuejin Wu; Min Liu; Lijun Wu; Jinying Lu; Po Bian
      Abstract: Publication date: Available online 6 September 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ting Wang, Wei Xu, Huasheng Li, Chenguang Deng, Hui Zhao, Yuejin Wu, Min Liu, Lijun Wu, Jinying Lu, Po Bian
      Controlled ecological life support systems (CELSS) will be an important feature of long-duration space missions of which higher plants are one of the indispensable components. Because of its pivotal role in enabling plants to cope with environmental stress, interplant communication might have important implications for the ecological stability of such CELSS. However, the manifestations of interplant communication in microgravity conditions have yet to be fully elucidated. To address this, a well-established Arabidopsis thaliana co-culture experimental system, in which UV-C-induced airborne interplant communication is evaluated by the alleviation of transcriptional gene silencing (TGS) in bystander plants, was placed in microgravity modeled by a two-dimensional rotating clinostat. Compared with plants under normal gravity, TGS alleviation in bystander plants was inhibited in microgravity. Moreover, TGS alleviation was also prevented when plants of the pgm-1 line, which are impaired in gravity sensing, were used in either the UV-C-irradiated or bystander group. In addition to the specific TGS-loci, interplant communication-shaped genome-wide DNA methylation in bystander plants was altered under microgravity conditions. These results indicate that interplant communications might be modified in microgravity. Time course analysis showed that microgravity interfered with both the production of communicative signals in UV-C-irradiated plants and the induction of epigenetic responses in bystander plants. This was further confirmed by the experimental finding that microgravity also prevented the response of bystander plants to exogenous methyl jasmonate (JA) and methyl salicylate (SA), two well-known airborne signaling molecules, and down-regulated JA and SA biosynthesis in UV-C-irradiated plants.

      PubDate: 2017-09-08T18:22:55Z
      DOI: 10.1016/j.mrfmmm.2017.09.001
  • Delayed effects of accelerated heavy ions on the induction of HPRT
           mutations in V79 hamster cells
    • Authors: Pavel Bláha; Nataliya A. Koshlan; Igor V. Koshlan; Daria V. Petrova; Yulia V. Bogdanova; Raisa D. Govorun; Viliam Múčka; Evgeny A. Krasavin
      Abstract: Publication date: Available online 31 August 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Pavel Bláha, Nataliya A. Koshlan, Igor V. Koshlan, Daria V. Petrova, Yulia V. Bogdanova, Raisa D. Govorun, Viliam Múčka, Evgeny A. Krasavin
      Fundamental research on the harmful effects of ionizing radiation on living cells continues to be of great interest. Recently, priority has been given to the study of high-charge and high-energy (HZE) ions that comprise a substantial part of the galactic cosmic ray (GCR) spectra that would be encountered during long-term space flights. Moreover, predictions of the delayed genetic effects of high linear energy transfer (LET) exposure is becoming more important as heavy ion therapy use is increasing. This work focuses mainly on the basic research on the delayed effects of HZE ions on V79 Chinese hamster cells, with emphasis on the induction of HPRT mutations after prolonged expression times (ET). The research was conducted under various irradiation conditions with accelerated ions 18O (E=35.2MeV/n), 20Ne (E=47.7MeV/n and 51.8MeV/n), and 11B (E=32.4MeV/n), with LET in the range from 49 to 149 keV/μm and with 60Co γ-rays. The HPRT mutant fractions (MF) were detected in irradiated cells in regular intervals during every cell culture recultivation (every 3 days) up to approximately 40days (70–80 generations) after irradiation. The MF maximum was reached at different ET depending on ionizing radiation characteristics. The position of the maximum was shifting towards longer ET with increasing LET. We speculate that the delayed mutations are created de novo and that they are the manifestation of genomic instability. Although the exact mechanisms involved in genomic instability initiation are yet to be identified, we hypothesize that differences in induction of delayed mutations by radiations with various LET values is related to variations in energy deposition along the particle track. A dose dependence of mutation yield is discussed as well.

      PubDate: 2017-09-03T18:10:12Z
      DOI: 10.1016/j.mrfmmm.2017.08.004
  • Investigating mutation-specific biological activities of small molecules
           using quantitative structure-activity relationship for epidermal growth
           factor receptor in cancer
    • Authors: P. Anoosha; R. Sakthivel; M. Michael Gromiha
      Abstract: Publication date: Available online 26 August 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): P. Anoosha, R. Sakthivel, M. Michael Gromiha
      Epidermal Growth Factor Receptor (EGFR) is a potential drug target in cancer therapy. Missense mutations play major roles in influencing the protein function, leading to abnormal cell proliferation and tumorigenesis. A number of EGFR inhibitor molecules targeting ATP binding domain were developed from the past two decades. Unfortunately, they become inactive due to resistance caused by new mutations in patients, and previous studies have also reported noticeable differences in inhibitor binding to distinct known driver mutants as well. Hence, there is a high demand for identification of EGFR mutation-specific inhibitors. In our present study, we derived a set of anti-cancer compounds with biological activities against eight typical EGFR known driver mutations and developed quantitative structure-activity relationship (QSAR) models for each separately. The compounds are grouped based on their functional scaffolds, which enhanced the correlation between compound features and respective biological activities. The models for different mutants performed well with a correlation coefficient, (r) in the range of 0.72–0.91 on jack-knife test. Further, we analyzed the selected features in different models and observed that hydrogen bond and aromaticity-related features play important roles in predicting the biological activity of a compound. This analysis is complimented with docking studies, which showed the binding patterns and interactions of ligands with EGFR mutants that could influence their activities.
      Graphical abstract image

      PubDate: 2017-09-03T18:10:12Z
      DOI: 10.1016/j.mrfmmm.2017.08.003
  • Role of specialized DNA polymerases in the limitation of replicative
           stress and DNA damage transmission
    • Authors: Elodie Bournique; Marina Dall’Osto; Jean-Sébastien Hoffmann; Valérie Bergoglio
      Abstract: Publication date: Available online 14 August 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Elodie Bournique, Marina Dall’Osto, Jean-Sébastien Hoffmann, Valérie Bergoglio
      Replication stress is a strong and early driving force for genomic instability and tumor development. Beside replicative DNA polymerases, an emerging group of specialized DNA polymerases is involved in the technical assistance of the replication machinery in order to prevent replicative stress and its deleterious consequences. During S-phase, altered progression of the replication fork by endogenous or exogenous impediments induces replicative stress, causing cells to reach mitosis with genomic regions not fully duplicated. Recently, specific mechanisms to resolve replication intermediates during mitosis with the aim of limiting DNA damage transmission to daughter cells have been identified. In this review, we detail the two major actions of specialized DNA polymerases that limit DNA damage transmission: the prevention of replicative stress by non-B DNA replication and the recovery of stalled replication forks.

      PubDate: 2017-08-24T17:24:33Z
      DOI: 10.1016/j.mrfmmm.2017.08.002
  • 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
  • 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
    • 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
  • 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
    • 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
    • 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
    • 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
           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
  • 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
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Heriot-Watt University
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