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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  [2970 journals]
  • Induction of Genomic Instability and Activation of Autophagy in Artificial
           Human Aneuploid Cells
    • Abstract: Publication date: Available online 14 June 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Kentaro Ariyoshi, Tomisato Miura, Kosuke Kasai, Yohei Fujishima, Mitsuo Oshimura, Mitsuaki A. Yoshida
      Chromosome missegregation can lead to a change in chromosome number known as aneuploidy. Although aneuploidy is a known hallmark of cancer cells, the various mechanisms by which altered gene and/or DNA copy number facilitate tumorigenesis remain unclear. To understand the effect of aneuploidy occurring in non-tumorigenic human breast epithelial cells, we generated clones harboring artificial aneuploidy using microcell-mediated chromosome transfer. Our results demonstrate that clones with artificial aneuploidy of chromosome 8 or chromosome 22 both show inhibited proliferation and genomic instability. Also, the increased autophagy was observed in the artificially aneuploidy clones, and inhibition of autophagy resulted in increased genomic instability and DNA damage. In addition, the intracellular levels of reactive oxygen species were up-regulated in the artificially aneuploid clones, and inhibition of autophagy further increased the production of reactive oxygen species. Together, these results suggest that even a single extraneous chromosome can induce genomic instability, and that autophagy triggered by aneuploidy-induced stress is a mechanism to protect cells bearing abnormal chromosome number.


      PubDate: 2016-06-15T21:05:51Z
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: July 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 789




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




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



      PubDate: 2016-05-30T18:44:40Z
       
  • Site-directed mutants of human RECQ1 reveal functional importance of the
           zinc binding domain
    • Abstract: Publication date: Available online 17 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Furqan Sami, Ronald K. Gary, Yayin Fang, Sudha Sharma
      RecQ helicases are a highly conserved family of ATP-dependent DNA-unwinding enzymes with key roles in DNA replication and repair in all kingdoms of life. The RECQ1 gene encodes the most abundant RecQ homolog in humans. Mutations in RECQ1 significantly increase breast cancer susceptibility. We engineered full-length RECQ1 harboring point mutations in the zinc-binding motif (amino acids 419-480) within the conserved RecQ-specific- C-terminal (RQC) domain known to be critical for diverse biochemical and cellular functions of RecQ helicases. Wild-type RECQ1 contains a zinc ion. Substitution of three of the four conserved cysteine residues that coordinate zinc severely impaired the ATPase and DNA unwinding activities but retained DNA binding and single strand DNA annealing activities. Furthermore, alteration of these residues attenuated zinc binding and significantly changed the overall conformation of full-length RECQ1 protein. In contrast, substitution of cysteine residue at position 471 resulted in a wild-type like RECQ1 protein. Differential contribution of the conserved cysteine residues to the structure and functions of the RECQ1 protein is also inferred by homology modeling. Overall, our results indicate that the zinc binding motif in the RQC domain of RECQ1 is a key structural element that is essential for the structure-functions of RECQ1. Given the recent association of RECQ1 mutations with breast cancer, these observations will contribute to understanding the molecular basis of RECQ1 functions in cancer etiology.


      PubDate: 2016-05-20T17:52:07Z
       
  • Abnormal mRNA Splicing but Normal Auditory Brainstem Response (ABR) in
           Mice with the Prestin (SLC26A5) IVS2-2A>G mutation
    • Abstract: Publication date: Available online 12 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jian Zhang, Ziyi Liu, Aoshuang Chang, Jie Fang, Yuqin Men, Yong Tian, Xiaomei Ouyang, Denise Yan, Aizhen Zhang, Xiaoyang Sun, Jie Tang, Xuezhong Liu, Jian Zuo, Jiangang Gao
      Prestin is critical to OHC somatic motility and hearing sensitivity in mammals. Several mutations of the human SLC26A5 gene have been associated with deafness. However, whether the IVS2-2A>G mutation in the human SLC26A5 gene causes deafness remains controversial. In this study, we created a mouse model in which the IVS2-2A>G mutation was introduced into the mouse Slc26a5 gene by gene targeting. The homozygous Slc26a5 mutant mice were viable and fertile and displayed normal hearing sensitivity by ABR threshold analysis. Whole-mount immunostaining using prestin antibody demonstrated that prestin was correctly targeted to the lateral wall of OHCs, and no obvious hair cell loss occurred in mutant mice. No significant difference in the amount of prestin protein was observed between mutants and controls using western blot analysis. In OHCs isolated from mutants, the NLC was also normal. However, we observed a splicing abnormality in the Slc26a5 mRNA of the mutant mice. Eleven nucleotides were missing from the 5' end of exon 3 in Slc26a5 mRNA, but the normal ATG start codon in exon 3 was still detected. Thus, the IVS2-2A>G mutation in the Slc26a5 gene is insufficient to cause hearing loss in mice.


      PubDate: 2016-05-15T17:31:07Z
       
  • Chromothripsis and Epigenetics in the Heritable Genotoxicity,
           Carcinogenicity and Fetotoxicity of Cannabis and Other Addictions.
    • Abstract: Publication date: Available online 4 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Albert Stuart Reece, Gary Kenneth Hulse
      The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule machinery of the mitotic spindle followed by haphazard chromosomal annealing, together with sophisticated insights from epigenetics, provide profound mechanistic insights into some of the most perplexing classical observations of addiction medicine, including cancerogenesis, the younger and aggressive onset of addiction-related carcinogenesis, the heritability of addictive neurocircuitry and cancers, and foetal malformations. Tetrahydrocannabinol (THC) and other addictive agents have been shown to inhibit tubulin polymerization which perturbs the formation and function of the microtubules of the mitotic spindle. This disruption of the mitotic machinery perturbs proper chromosomal segregation during anaphase and causes micronucleus formation which is the primary locus and cause of the chromosomal pulverization of chromothripsis and downstream genotoxic events including oncogene induction and tumour suppressor silencing. Moreover the complementation of multiple positive cannabis-cancer epidemiological studies, and replicated dose-response relationships with established mechanisms fulfils causal criteria. This information is also consistent with data showing acceleration of the aging process by drugs of addiction including alcohol, tobacco, cannabis, stimulants and opioids. THC shows a non-linear sigmoidal dose-response relationship in multiple pertinent in vitro and preclinical genotoxicity assays, and in this respect is similar to the serious major human mutagen thalidomide. Rising community exposure, tissue storage of cannabinoids, and increasingly potent phytocannabinoid sources, suggests that the threshold mutagenic dose for cancerogenesis will increasingly be crossed beyond the developing world, and raise transgenerational transmission of teratogenicity as an increasing concern.
      Graphical abstract image

      PubDate: 2016-05-06T16:08:59Z
       
  • Different repair kinetic of DSBs induced by mitomycin C in peripheral
           lymphocytes of obese and normal weight adolescents
    • Abstract: Publication date: Available online 3 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Alessia Azzarà, Chiara Pirillo, Caterina Giovannini, Giovanni Federico, Roberto Scarpato
      In 2013, 42 million children under the age of 5 years were overweight or obese. In the context of obesity, we recently showed that (1) peripheral lymphocytes of obese children/adolescents had an 8-fold increase in double strand breaks (DSBs), expressed as g-H2AX foci, than normal weight adolescents, and (2) 30% of the damage was retained into chromosome mutations. Thus, we investigated DSBs repair efficiency in a group of obese adolescents assessing the kinetic of H2AX phosphorylation in mitomycin C (MMC)-treated lymphocytes harvested 2 h- or 4 h-post mutagen treatment. According to our previous studies, these harvesting times represent the peak of DSBs induction and the time in which an appreciable DSBs reduction was observed. In addition, we evaluated the expression of the high mobility group box-1 protein (HMGB1), a chromatin remodelling protein involved in DSBs repair and obesity. Compared to normal weight adolescents, obese subjects 1) showed higher levels of g-H2AX foci at either 2 h- (0.239±0.041 vs. 0.473±0.048, P=0.0016) or 4 h- (0.150±0.026 vs. 0.255±0.030, P=0.0198) post mutagen treatment, and 2) have repaired a greater amount of the initial lesions (0.088±0.033 vs. 0.218±0.045, P=0.0408). Concordantly, 1) HMGB1 levels of obese individuals increased and decreased at 2h- or 4 h-post mutagen treatment, respectively, and 2) the opposite occurred for the normal weight adolescents where the protein was down-expressed at 2h and over-expressed at 4h. In conclusion, lymphocytes of obese and normal weight adolescents showed a distinct temporal kinetic of repairing MMC-induced DSBs, together with a different expression of HMGB1. The finding that obesity may modulate the repair of DNA damage induced in lymphocytes by genotoxic agents should be confirmed by further experiments.


      PubDate: 2016-05-06T16:08:59Z
       
  • Signaling factors and pathways of α-particle irradiation induced
           bilateral bystander responses between Beas-2B and U937 cells
    • Abstract: Publication date: Available online 2 May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jiamei Fu, Juan Wang, Xiangdong Wang, Ping Wang, Jinping Xu, Cuiping Zhou, Yang Bai, Chunlin Shao
      Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral bystander responses that the release of TNF-α and IL-8 regulated by MAPK and NF-κB pathways synergistically increased cellular injury after α-particle irradiation.


      PubDate: 2016-05-02T15:36:53Z
       
  • Reprint of “DNA, the central molecule of aging”
    • Abstract: Publication date: Available online 28 April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Peter Lenart, Lumir Krejci
      Understanding the molecular mechanism of aging could have enormous medical implications. Despite a century of research, however, there is no universally accepted theory regarding the molecular basis of aging. On the other hand, there is plentiful evidence suggesting that DNA constitutes the central molecule in this process. Here, we review the roles of chromatin structure, DNA damage, and shortening of telomeres in aging and propose a hypothesis for how their interplay leads to aging phenotypes.


      PubDate: 2016-05-02T15:36:53Z
       
  • UV-C-Induced alleviation of transcriptional gene silencing through
           plant–plant communication: Key roles of jasmonic acid and salicylic
           acid pathways
    • Abstract: Publication date: Available online 27 April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Wei Xu, Ting Wang, Shaoxin Xu, Fanghua Li, Chenguang Deng, Lijun Wu, Yuejin Wu, Po Bian
      Plant stress responses at the epigenetic level are expected to allow more permanent changes of gene expression and potentially long-term adaptation. While it has been reported that plants subjected to adverse environments initiate various stress responses in their neighboring plants, little is known regarding epigenetic responses to external stresses mediated by plant–plant communication. In this study, we show that DNA repetitive elements of Arabidopsis thaliana, whose expression is inhibited epigenetically by transcriptional gene silencing (TGS) mechanism, are activated by UV-C irradiation through airborne plant–plant and plant–plant–plant communications, accompanied by DNA demethylation at CHH sites. Moreover, the TGS is alleviated by direct treatments with exogenous methyl jasmonate (MeJA) and methyl salicylate (MeSA). Further, the plant–plant and plant–plant–plant communications are blocked by mutations in the biosynthesis or signaling of jasmonic acid (JA) or salicylic acid (SA), indicating that JA and SA pathways are involved in the interplant communication for epigenetic responses. For the plant–plant–plant communication, stress cues are relayed to the last set of receiver plants by promoting the production of JA and SA signals in relaying plants, which exhibit upregulated expression of genes for JA and SA biosynthesis and enhanced emanation of MeJA and MeSA.


      PubDate: 2016-05-02T15:36:53Z
       
  • Simple sequence repeat variations expedite phage divergence: mechanisms of
           indels and gene mutations
    • Abstract: Publication date: Available online 14 April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Tiao-Yin Lin
      Phages are the most abundant biological entities and influence prokaryotic communities on Earth. Comparing closely related genomes sheds light on molecular events shaping phage evolution. Simple sequence repeat (SSR) variations impart over half of the genomic changes between T7M and T3, indicating an important role of SSRs in accelerating phage genetic divergence. Differences in coding and noncoding regions of phages infecting different hosts, coliphages T7M and T3, Yersinia phage φYeO3-12, and Salmonella phage φSG-JL2, frequently arise from SSR variations. Such variations modify noncoding and coding regions; the latter efficiently changes multiple amino acids, thereby hastening protein evolution. Four classes of events are found to drive SSR variations: insertion/deletion of SSR units, expansion/contraction of SSRs without alteration of genome length, changes of repeat motifs, and generation/loss of repeats. The categorization demonstrates the ways SSRs mutate in genomes during phage evolution. Indels are common constituents of genome variations and human diseases, yet, how they occur without preexisting repeat sequence is less understood. Non-repeat-unit-based misalignment-elongation (NRUBME) is proposed to be one mechanism for indels without adjacent repeats. NRUBME or consecutive NRUBME may also change repeat motifs or generate new repeats. NRUBME invoking a non-Watson-Crick base pair explains insertions that initiate mononucleotide repeats. Furthermore, NRUBME successfully interprets many inexplicable human di- to tetranucleotide repeat generations. This study provides the first evidence of SSR variations expediting phage divergence, and enables insights into the events and mechanisms of genome evolution. NRUBME allows us to emulate natural evolution to design indels for various applications.
      Graphical abstract image

      PubDate: 2016-04-19T12:24:26Z
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: May 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 787




      PubDate: 2016-04-09T10:34:02Z
       
  • Charged Particle Mutagenesis at Low Dose and Fluence in Mouse Splenic T
           Cells
    • Abstract: Publication date: Available online 29 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Dmytro Grygoryev, Stacey Gauny, Michael Lasarev, Anna Ohlrich, Amy Kronenberg, Mitchell S. Turker
      High-energy heavy charged particles (HZE ions) found in the deep space environment can significantly affect human health by inducing mutations and related cancers. To better understand the relation between HZE ion exposure and somatic mutation, we examined cell survival fraction, Aprt mutant frequencies, and the types of mutations detected for mouse splenic T cells exposed in vivo to graded doses of densely ionizing 48Ti ions (1GeV/amu, LET=107 keV/μm), 56Fe ions (1GeV/amu, LET=151 keV/μm) ions, or sparsely ionizing protons (1GeV, LET=0.24 keV/μm). The lowest doses for 48Ti and 56Fe ions were equivalent to a fluence of approximately 1 or 2 particle traversals per nucleus. In most cases, Aprt mutant frequencies in the irradiated mice were not significantly increased relative to the controls for any of the particles or doses tested at the pre-determined harvest time (3-5 months after irradiation). Despite the lack of increased Aprt mutant frequencies in the irradiated splenocytes, a molecular analysis centered on chromosome 8 revealed the induction of radiation signature mutations (large interstitial deletions and complex mutational patterns), with the highest levels of induction at 2 particles nucleus for the 48Ti and 56Fe ions. In total, the results show that densely ionizing HZE ions can induce characteristic mutations in splenic T cells at low fluence, and that at least a subset of radiation-induced mutant cells are stably retained despite the apparent lack of increased mutant frequencies at the time of harvest.


      PubDate: 2016-03-30T08:48:02Z
       
  • Vincristine-induced bystander effect in human lymphocytes
    • Abstract: Publication date: Available online 25 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Serena Testi, Alessia Azzarà, Caterina Giovannini, Sara Lombardi, Simona Piaggi, Maria Sole Facioni, Roberto Scarpato
      Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5±1.41at 6μM, 22±2.12at 12μM or 28.25±5.13at 15μM vs. a control value of 4.75±1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75±0.88at 0.0μM, 27.25±2.30at 0.4μM, 46.25±1.94at 0.8μM, 98.25±7.25at 1.6μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the bystander effect induced by VCR. In fact, we observed an increased level of ROS, IL-32 and TGF-β in the CM from VCR treated cultures, not present in MMC treated cultures.


      PubDate: 2016-03-26T08:06:02Z
       
  • Lack of increased DNA double-strand breaks in peripheral blood mononuclear
           cells of individuals from high level natural radiation areas of Kerala
           coast in India
    • Abstract: Publication date: Available online 25 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Vinay Jain, P.R.Vivek Kumar, P.K.M. Koya, G. Jaikrishan, Birajalaxmi Das
      The high level natural radiation area (HLNRA) of Kerala is a 55km long and 0.5km wide strip in south west coast of India. The level of background radiation in this area varies from<1.0mGy/year to 45.0mGy/year. It offers unique opportunity to study the effect of chronic low dose/low dose-rate radiation directly on human population. Spontaneous level of DNA double strand breaks (DSBs) was quantified in peripheral blood mononuclear cells of 91 random individuals from HLNRA (N=61, mean age: 36.1±7.43years) and normal level natural radiation area (NLNRA) (N=30, mean age: 35.5±6.35years) using gamma-H2AX as a marker. The mean annual dose received by NLNRA and HLNRA individuals was 1.28±0.086mGy/year and 8.28±4.96mGy/year, respectively. The spontaneous frequency of DSBs in terms of gamma-H2AX foci among NLNRA and HLNRA individuals were 0.095±0.009 and 0.084±0.004 per cell (P=0.22). The individuals from HLNRA were further classified as low dose group (LDG, 1.51-5.0mGy/year, mean dose: 2.63±0.76mGy/year) and high dose group (HDG,>5.0mGy/year, mean dose: 11.04±3.57mGy/year). The spontaneous frequency of gamma-H2AX foci per cell in NLNRA, LDG and HDG was observed to be 0.095±0.009, 0.096±0.008 and 0.078±0.004 respectively. Individuals belonging to HDG of HLNRA showed marginally lower frequency of DSBs as compared to NLNRA and LDG of HLNRA. This could be suggestive of either lower induction or better repair of DSBs in individuals from HDG of HLNRA. The present study indicated that 5.0mGy/year could be a possible threshold dose for DSB induction at chronic low-dose radiation exposure in vivo. However, further studies on DNA damage induction and repair kinetics are required to draw firm conclusions.


      PubDate: 2016-03-26T08:06:02Z
       
  • Implications of genotypic differences in the generation of a urinary
           metabolomics radiation signature.
    • Abstract: Publication date: Available online 25 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Evagelia C. Laiakis, Evan L. Pannkuk, Maria Elena Diaz-Rubio, Yi-Wen Wang, Tytus D. Mak, Cynthia M. Simbulan-Rosenthal, David J. Brenner, Albert J. Fornace
      The increased threat of radiological terrorism and accidental nuclear exposures, together with increased usage of radiation-based medical procedures, has made necessary the development of minimally invasive methods for rapid identification of exposed individuals. Genetically predisposed radiosensitive individuals comprise a significant number of the population and require specialized attention and treatments after such events. Metabolomics, the assessment of the collective small molecule content in a given biofluid or tissue has proven effective in the rapid identification of radiation biomarkers and metabolic perturbations. To investigate how the genotypic background may alter the ionizing radiation (IR) signature, we analyzed urine from Parp1−/− mice, as a model radiosensitive genotype, exposed to IR by utilizing the analytical power of liquid chromatography coupled with mass spectrometry (LC–MS), as urine has been thoroughly investigated in wild type (WT) mice in previous studies from our laboratory. Samples were collected at days one and three after irradiation, time points that are important for the early and efficient triage of exposed individuals. Time- dependent perturbations in metabolites were observed in the tricarboxylic acid pathway (TCA). Other differentially excreted metabolites included amino acids and metabolites associated with dysregulation of energy metabolism pathways. Time-dependent apoptotic pathway activation between WT and mutant mice following IR exposure may explain the altered excretion patterns, although the origin of the metabolites remains to be determined. This first metabolomics study in urine from radiation exposed genetic mutant animal models provides evidence that this technology can be used to dissect the effects of genotoxic agents on metabolism by assessing easily accessible biofluids and identify biomarkers of radiation exposure. Applications of metabolomics could be incorporated in the future to further elucidate the effects of IR on the metabolism of Parp1−/− genotype by assessing individual tissues.


      PubDate: 2016-03-26T08:06:02Z
       
  • Nucleotide excision repair deficiency increases levels of acrolein-derived
           cyclic DNA adduct and sensitizes cells to apoptosis induced by
           docosahexaenoic acid and acrolein
    • Abstract: Publication date: Available online 16 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jishen Pan, Elizabeth Sinclair, Zhuoli Xuan, Marcin Dyba, Ying Fu, Supti Sen, Deborah Berry, Karen Creswell, Jiaxi Hu, Rabindra Roy, Fung-Lung Chung
      The acrolein derived cyclic 1,N2-propanodeoxyguanosine adduct (Acr-dG), formed primarily from ω-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) under oxidative conditions, while proven to be mutagenic, is potentially involved in DHA-induced apoptosis. The latter may contribute to the chemopreventive effects of DHA. Previous studies have shown that the levels of Acr-dG are correlated with apoptosis induction in HT29 cells treated with DHA. Because Acr-dG is shown to be repaired by the nucleotide excision repair (NER) pathway, to further investigate the role of Acr-dG in apoptosis, in this study, NER-deficient XPA and its isogenic NER-proficient XAN1 cells were treated with DHA. The Acr-dG levels and apoptosis were sharply increased in XPA cells, but not in XAN1 cells when treated with 125μM of DHA. Because DHA can induce formation of various DNA damage, to specifically investigate the role of Acr-dG in apoptosis induction, we treated XPA knockdown HCT–116+ch3 cells with acrolein. The levels of both Acr-dG and apoptosis induction increased significantly in the XPA knockdown cells. These results clearly demonstrate that NER deficiency induces higher levels of Acr-dG in cells treated with DHA or acrolein and sensitizes cells to undergo apoptosis in a correlative manner. Collectively, these results support that Acr-dG, a ubiquitously formed mutagenic oxidative DNA adduct, plays a role in DHA-induced apoptosis and suggest that it could serve as a biomarker for the cancer preventive effects of DHA.


      PubDate: 2016-03-17T05:55:03Z
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 786




      PubDate: 2016-03-13T16:51:39Z
       
  • Gene Mutations in Rats with Moderate Malnutrition
    • Abstract: Publication date: Available online 8 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): M.Monserrat Pacheco-Martínez, Edith Cortés-Barberena, Elsa Cervantes-Ríos, María del Carmen García-Rodríguez, Leonor Rodríguez-Cruz, Rocío Ortiz-Muñiz
      The relationship between malnutrition and genetic damage has been widely studied in human and animal models, leading to the observation that interactions between genotoxic exposure and micronutrient status appear to affect genomic stability. A new assay has been developed that uses the phosphatidylinositol glycan class A gene (Pig-a) as a reporter for measuring in vivo gene mutation. The Pig-a assay can be employed to evaluate mutant frequencies (MFs) in peripheral blood reticulocytes (RETs) and erythrocytes (RBCs) using flow cytometry. In the present study, we assessed the effects of malnutrition on mutagenic susceptibility by exposing undernourished (UN) and well-nourished (WN) rats to N-ethyl-N-nitrosourea (ENU) and measuring Pig-a MFs. Two week-old UN and WN male Han-Wistar rats were treated daily with 0, 20, or 40mg/kg ENU for 3 consecutive days. Blood was collected from the tail vein one day before ENU treatment (Day −1) and after ENU administration on Days 7, 14, 21, 28, 35, 42, 49, 56 and 63. Pig-a MFs were measured in RETs and RBCs as the RETCD59− and RBCCD59− frequencies. In the vehicle control groups, the frequencies of mutant RETs and RBCs were significantly higher in UN rats compared with WN rats at all sampling times. The ENU treatments increased RET and RBC MFs starting at Day 7. Although ENU-induced Pig-a MFs were consistently lower in UN rats than in WN rats, these differences were not significant. To understand these responses, further studies should use other mutagens and nucleated surrogate cells and examine the types of mutations induced in UN and WN rats.


      PubDate: 2016-03-13T16:51:39Z
       
  • Radiation-induced changes in DNA methylation of repetitive elements in the
           mouse heart
    • Abstract: Publication date: Available online 2 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Igor Koturbash, Isabelle R. Miousse, Vijayalakshmi Sridharan, Etienne Nzabarushimana, Charles M. Skinner, Stepan B. Melnyk, Oleksandra Pavliv, Martin Hauer-Jensen, Gregory A. Nelson, Marjan Boerma
      DNA methylation is a key epigenetic mechanism, needed for proper control over the expression of genetic information and silencing of repetitive elements. Exposure to ionizing radiation, aside from its strong genotoxic potential, may also affect the methylation of DNA, within the repetitive elements, in particular. In this study, we exposed C57BL/6J male mice to low absorbed mean doses of two types of space radiation − proton (0.1Gy, 150 MeV, dose rate 0.53±0.08Gy/min), and heavy iron ions (56Fe) (0.5Gy, 600 MeV/n, dose rate 0.38±0.06Gy/min). Radiation-induced changes in cardiac DNA methylation associated with repetitive elements were detected. Specifically, modest hypomethylation of retrotransposon LINE-1 was observed at day 7 after irradiation with either protons or 56Fe. This was followed by LINE-1, and other retrotransposons, ERV2 and SINE B1, as well as major satellite DNA hypermethylation at day 90 after irradiation with 56Fe. These changes in DNA methylation were accompanied by alterations in the expression of DNA methylation machinery and affected the one-carbon metabolism pathway. Furthermore, loss of transposable elements expression was detected in the cardiac tissue at the 90-day time-point, paralleled by substantial accumulation of mRNA transcripts, associated with major satellites. Given that the one-carbon metabolism pathway can be modulated by dietary modifications, these findings suggest a potential strategy for the mitigation and, possibly, prevention of the negative effects exerted by ionizing radiation on the cardiovascular system. Additionally, we show that the methylation status and expression of repetitive elements may serve as early biomarkers of exposure to space radiation.


      PubDate: 2016-03-03T13:43:18Z
       
  • H2A/K pseudogene mutation may promote cell proliferation
    • Abstract: Publication date: Available online 2 March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jisheng Guo, Ruirui Jing, Xin Lv, Xiaoyue Wang, Junqiang Li, Lin Li, Cuiling Li, Daoguang Wang, Baibing Bi, Xinjun Chen, Jinghua Yang
      Little attention has been paid to the histone H2A/K pseudogene. Results from our laboratory showed that 7 of 10 kidney cancer patients carried a mutant H2A/K pseudogene; therefore, we were interested in determining the relationship between mutant H2A/K and cell proliferation. We used shotgun and label-free proteomics methods to study whether mutant H2A/K lncRNAs affected cell proliferation. Quantitative proteomic analysis indicated that the expression of mutant H2A/K lncRNAs resulted in the upregulation of many oncogenes, which promoted cell proliferation. Further interaction analyses revealed that a proliferating cell nuclear antigen (PCNA)-protein interaction network, with PCNA in the center, contributes to cell proliferation in cells expressing the mutant H2A/K lncRNAs. Western blotting confirmed the critical upregulation of PCNA by mutant H2A/K lncRNA expression. Finally, the promotion of cell proliferation by mutant H2A/K lncRNAs (C290T, C228A and A45G) was confirmed using cell proliferation assays. Although we did not determine the exact mechanism by which the oncogenes were upregulated by the mutant H2A/K lncRNAs, we confirmed that the mutant H2A/K lncRNAs promoted cell proliferation by upregulating PCNA and other oncogenes. The hypothesis that cell proliferation is promoted by the mutant H2A/K lncRNAs was supported by the protein expression and cell proliferation assay results. Therefore, mutant H2A/K lncRNAs may be a new factor in renal carcinogenesis.


      PubDate: 2016-03-03T13:43:18Z
       
  • Differences in the Origins of Kinetochore-positive and
           Kinetochore-negative Micronuclei: A Live Cell Imaging Study
    • Abstract: Publication date: Available online 23 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Erkang Jiang
      Micronuclei (MNi) are extensively used to evaluate genotoxicity and chromosomal instability. Classification of kinetochore-negative (K-MNi) and kinetochore-positive micronuclei (K+MNi) improves the specificity and sensitivity of the micronucleus (MN) test; however, the fundamental differences in the origins of K-MNi and K+MNi have not been addressed due to the limitations of traditional methods. In the current study, HeLa CENP B-GFP H2B-mCherry cells were constructed in which histone 2B (H2B) and centromere protein B (CENP B) were expressed as fusion proteins to monomeric Cherry (mCherry) and EGFP, respectively. MNi were identified using H2B-mCherry; K+MN contained CENP B-GFP, while K-MN did not. Long-term live cell imaging was conducted to examine MN formation in the dual-color fluorescent HeLa cells. The results suggested that K-MNi were derived from kinetochore-negative displaced chromosomes (K-DCs), kinetochore-negative lagging chromosomes (K-LCs) and fragments of broken chromosome bridges (CBs) during late mitotic stages. The results also indicated that K+MNi are derived from kinetochore-positive displaced chromosomes (K+DCs), kinetochore-positive lagging chromosomes (K+LCs), and fragments of broken CBs. Different aberrant chromosomes emerged during mitosis at different frequencies and developed into K-MNi and/or K+MNi in the daughter cells at different rates. K+LCs formed K+MNi at a higher frequency than K+DCs, and K-LCs formed K-MNi at a higher rate than K-DCs; however, broken CBs transformed into K-MNi and/or K+MNi. In summary, these results show that K-MNi and K+MNi have different origins in HeLa cells and that each mechanism of MN formation contributes differently to the overall number of K-MNi and K+MNi.


      PubDate: 2016-02-27T08:44:12Z
       
  • Increased MTHFR promoter methylation in mothers of Down syndrome
           individuals
    • Abstract: Publication date: Available online 22 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Fabio Coppedè, Maria Denaro, Pierpaola Tannorella, Lucia Migliore
      Despite that advanced maternal age at conception represents the major risk factor for the birth of a child with Down syndrome (DS), most of DS babies are born from women aging less than 35 years. Studies performed in peripheral lymphocytes of those women revealed several markers of global genome instability, including an increased frequency of micronuclei, shorter telomeres and impaired global DNA methylation. Furthermore, young mothers of DS individuals (MDS) are at increased risk to develop dementia later in life, suggesting that they might be “biologically older” than mothers of euploid babies of similar age. Mutations in folate pathway genes, and particularly in the methylenetetrahydrofolate reductase (MTHFR) one, have been often associated with maternal risk for a DS birth as well as with risk of dementia in the elderly. Recent studies pointed out that also changes in MTHFR methylation levels can contribute to human disease, but nothing is known about MTHFR methylation in MDS tissues. We investigated MTHFR promoter methylation in DNA extracted from perypheral lymphocytes of 40 MDS and 44 matched control women that coinceived their children before 35 years of age, observing a significantly increased MTHFR promoter methylation in the first group (33.3±8.1% vs. 28.3±5.8%; p =0.001). In addition, the frequency of micronucleated lymphocytes was available from the women included in the study, was higher in MDS than control mothers (16.1±8.6‰ vs. 10.5±4.3‰; p =0.0004), and correlated with MTHFR promoter methylation levels (r =0.33; p =0.006). Present data suggest that MTHFR epimutations are likely to contribute to the increased genomic instability observed in cells from MDS, and could play a role in the risk of birth of a child with DS as well as in the onset of age related diseases in those women.


      PubDate: 2016-02-27T08:44:12Z
       
  • TRAIL causes deletions at the HPRT and TK1 loci of clonogenically
           competent cells
    • Abstract: Publication date: Available online 18 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mark A. Miles, Tanmay M. Shekhar, Nathan E. Hall, Christine J. Hawkins
      When chemotherapy and radiotherapy are effective, they function by inducing DNA damage in cancerous cells, which respond by undergoing apoptosis. Some adverse effects can result from collateral destruction of non-cancerous cells, via the same mechanism. Therapy-related cancers, a particularly serious adverse effect of anti-cancer treatments, develop due to oncogenic mutations created in non-cancerous cells by the DNA damaging therapies used to eliminate the original cancer. Physiologically achievable concentrations of direct apoptosis inducing anti-cancer drugs that target Bcl-2 and IAP proteins possess negligible mutagenic activity, however death receptor agonists like TRAIL/Apo2L can provoke mutations in surviving cells, probably via caspase-mediated activation of the nuclease CAD. In this study we compared the types of mutations sustained in the HPRT and TK1 loci of clonogenically competent cells following treatment with TRAIL or the alkylating agent ethyl methanesulfonate (EMS). As expected, the loss-of-function mutations in the HPRT or TK1 loci triggered by exposure to EMS were almost all transitions. In contrast, only a minority of the mutations identified in TRAIL-treated clones lacking HPRT or TK1 activity were substitutions. Almost three quarters of the TRAIL-induced mutations were partial or complete deletions of the HPRT or TK1 genes, consistent with sub-lethal TRAIL treatment provoking double strand breaks, which may be mis-repaired by non-homologous end joining (NHEJ). Mis-repair of double-strand breaks following exposure to chemotherapy drugs has been implicated in the pathogenesis of therapy-related cancers. These data suggest that TRAIL too may provoke oncogenic damage to the genomes of surviving cells.
      Graphical abstract image

      PubDate: 2016-02-22T06:12:11Z
       
  • FANCJ at the FORK
    • Abstract: Publication date: Available online 17 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Sharon B. Cantor, Sumeet Nayak



      PubDate: 2016-02-18T03:19:08Z
       
  • DNA double strand break repair, aging and the chromatin connection
    • Abstract: Publication date: Available online 15 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Vera Gorbunova, Andrei Seluanov
      Are DNA damage and mutations possible causes or consequences of aging' This question has been hotly debated by biogerontologists for decades. The importance of DNA damage as a possible driver of the aging process went from being widely recognized to then forgotten, and is now slowly making a comeback. DNA double strand breaks (DSBs) are particularly relevant to aging because of their toxicity, increased frequency with age and the association of defects in their repair with premature aging. Recent studies expand the potential impact of DNA damage and mutations on aging by linking DNA DSB repair and age-related chromatin changes. There is overwhelming evidence that increased DNA damage and mutations accelerate aging. However, an ultimate proof of causality would be to show that enhanced genome and epigenome stability delays aging. This is not an easy task, as improving such complex biological processes is infinitely more difficult than disabling it. We will discuss the possibility that animal models with enhanced DNA repair and epigenome maintenance will be generated in the near future.


      PubDate: 2016-02-18T03:19:08Z
       
  • Aldehydes with high and low toxicities inactivate cells by damaging
           distinct cellular targets
    • Abstract: Publication date: Available online 15 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ming-Zhang Xie, Mahmoud I. Shoulkamy, Amir M.H. Salem, Shunya Oba, Mizuki Goda, Toshiaki Nakano, Hiroshi Ide
      Aldehydes are genotoxic and cytotoxic molecules and have received considerable attention for their associations with the pathogenesis of various human diseases. In addition, exposure to anthropogenic aldehydes increases human health risks. The general mechanism of aldehyde toxicity involves adduct formation with biomolecules such as DNA and proteins. Although the genotoxic effects of aldehydes such as mutations and chromosomal aberrations are directly related to DNA damage, the role of DNA damage in the cytotoxic effects of aldehydes is poorly understood because concurrent protein damage by aldehydes has similar effects. In this study, we have analysed how saturated and α,β-unsaturated aldehydes exert cytotoxic effects through DNA and protein damage. Interestingly, DNA repair is essential for alleviating the cytotoxic effect of weakly toxic aldehydes such as saturated aldehydes but not highly toxic aldehydes such as long α,β-unsaturated aldehydes. Thus, highly toxic aldehydes inactivate cells exclusively by protein damage. Our data suggest that DNA interstrand crosslinks, but not DNA-protein crosslinks and DNA double-strand breaks, are the critical cytotoxic DNA damage induced by aldehydes. Further, we show that the depletion of intracellular glutathione and the oxidation of thioredoxin 1 partially account for the DNA damage-independent cytotoxicity of aldehydes. On the basis of these findings, we have proposed a mechanistic model of aldehyde cytotoxicity mediated by DNA and protein damage.


      PubDate: 2016-02-18T03:19:08Z
       
  • F8 gene mutation profile in Indian hemophilia A patients: identification
           of 23 novel mutations and Factor VIII inhibitor risk association
    • Abstract: Publication date: Available online 10 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Patricia Pinto, Kanjaksha Ghosh, Shrimati Shetty
      ‘FVIII Inhibitors’, especially in severe hemophilia A (HA) patients, is a serious adverse effect that complicates their clinical management. Many genetic and non-genetic risk factors have been proposed for FVIII inhibitor development, diverse in different population groups. This is the first study in Indian hemophiliacs that analyses inhibitor risk in relation to the complete F8 mutation profile, in a case-control study that included 145 Indian severe HA patients, i.e. 69 inhibitor positive (with 18 inhibitor concordant/discordant family members), and 58 inhibitor negative patients, after informed consent. While 53.54% (68/127) index cases were positive for intron 22 or intron 1 inversions, 55 causative F8 mutations were detected in the 59 inversion negative patients, of which 23 were novel mutations (in 24 patients) and 32 were reported earlier (in 35 patients). A higher incidence of mutations, in the C1 and C2 domains in inhibitor positive patients, and in the A1 domain in inhibitor negative patients was observed, though not significantly different. The study suggests that large F8 rearrangements (significantly higher in the inhibitor positive patients) pose the highest risk, while missense mutations (significantly higher in the inhibitor negative patients) pose the lowest risk of inhibitor development in Indian hemophilia A patients.


      PubDate: 2016-02-14T01:43:46Z
       
  • DNA, the central molecule of aging
    • Abstract: Publication date: April 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 786
      Author(s): Peter Lenart, Lumir Krejci
      Understanding the molecular mechanism of aging could have enormous medical implications. Despite a century of research, however, there is no universally accepted theory regarding the molecular basis of aging. On the other hand, there is plentiful evidence suggesting that DNA constitutes the central molecule in this process. Here, we review the roles of chromatin structure, DNA damage, and shortening of telomeres in aging and propose a hypothesis for how their interplay leads to aging phenotypes.


      PubDate: 2016-02-10T00:29:52Z
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: February–March 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 784–785




      PubDate: 2016-02-10T00:29:52Z
       
  • A new MLPA-based method for the detection of acute myeloid
           leukemia-specific NPM1 mutations and simultaneous analysis of gene copy
           number alterations
    • Abstract: Publication date: Available online 4 February 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Malgorzata Marcinkowska-Swojak, Luiza Handschuh, Pawel Wojciechowski, Michal Goralski, Kamil Tomaszewski, Maciej Kazmierczak, Krzysztof Lewandowski, Mieczyslaw Komarnicki, Jacek Blazewicz, Marek Figlerowicz, Piotr Kozlowski
      The NPM1 gene encodes nucleophosmin, a protein involved in multiple cell functions and carcinogenesis. Mutation of the NPM1 gene, causing delocalization of the protein, is the most frequent genetic lesion in acute myeloid leukemia (AML); it is considered a founder event in AML pathogenesis and serves as a favorable prognostic marker. Moreover, in solid tumors and some leukemia cell lines, overexpression of the NPM1 gene is commonly observed. Therefore, the purpose of this study was to develop a new method for the detection of NPM1 mutations and the simultaneous analysis of copy number alterations (CNAs), which may underlie NPM1 gene expression deregulation. To address both of the issues, we applied a strategy based on multiplex ligation-dependent probe amplification (MLPA). A designed NPM1mut+ assay enables the detection of three of the most frequent NPM1 mutations: A, B and D. The accuracy of the assay was tested using a group of 83 samples from Polish patients with AML and other blood-proliferative disorders. To verify the results, we employed traditional Sanger sequencing and next-generation transcriptome sequencing. With the use of the NPM1mut+ assay, we detected mutations A, D and B in 14, 1 and 0 of the analyzed samples, respectively. All of these mutations were confirmed by complementary sequencing approaches, proving the 100% specificity and sensitivity of the proposed test. The performed sequencing analysis allowed the identification of two additional rare mutations (I and ZE). All of the mutations were identified exclusively in AML cases, accounting for 25% of those cases. We did not observe any CNAs (amplifications) of the NPM1 gene in the studied samples, either with or without the mutation. The presented method is simple, reliable and cost-effective. It can be easily introduced into clinical practice or developed to target both less-frequent mutations in the NPM1 gene and other cancer-related genes.
      Graphical abstract image

      PubDate: 2016-02-10T00:29:52Z
       
  • Genetic variants in multisynthetase complex genes are associated with DNA
           damage levels in Chinese populations
    • Abstract: Publication date: Available online 25 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jia Liu, Meng Zhu, Weihong Chen, Kaipeng Xie, Wei Shen, Jing Yuan, Yang Cheng, Liguo Geng, Yuzhuo Wang, Guangfu Jin, Juncheng Dai, Hongxia Ma, Jiangbo Du, Meilin Wang, Zhengdong Zhang, Zhibin Hu, Tangchun Wu, Hongbing Shen
      Aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multi-functional proteins (AIMPs) form a multisynthetase complex (MSC) and play an important role in the process of DNA damage repair. We hypothesized that genetic variants in key ARSs and AIMPs might regulate the DNA damage response. Therefore, we systematically screened 23 potentially functional polymorphisms in MSC genes and evaluated the association between the genetic variants and DNA damage levels in 307 subjects from three cities in southern, central and northern China (Zhuhai, Wuhan and Tianjin, respectively). We examined personal 24-h PM2.5 exposure levels and DNA damage levels in peripheral blood lymphocytes for each subject. We found that the variant allele of rs12199241 in AIMP3 was significantly associated with DNA damage levels (β =0.343, 95%CI: 0.133–0.554, P = 0.001). Meanwhile, the results of rs5030754 in EPRS and rs3784929 in KARS indicated their suggestive roles in DNA damage processes (β =0.331, 95%CI: 0.062–0.599, P = 0.016 for rs5030754; β =0.192, 95%CI: 0.016–0.368, P = 0.033 for rs3784929, respectively). After multiple testing, rs12199241 was still significantly associated with DNA damage levels. Combined analysis of these three polymorphisms showed a significant allele-dosage association between the number of risk alleles and higher DNA damage levels (P trend <0.001). These findings indicate that genetic variants in MSC genes may account for PM2.5-modulated DNA damage levels in Chinese populations.


      PubDate: 2016-01-29T22:15:47Z
       
  • Identification of six novel mutations in BCKDHA gene for classic form of
           maple syrup urine disease in Iranian patients and their in silico analysis
           
    • Abstract: Publication date: Available online 25 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Maryam Abiri, Razieh Karamzadeh, Morteza Karimipoor, Shirin Ghadami, Mohammad Reza Alaei, Samira Dabagh Bagheri, Hamideh Bagherian, Aria Setoodeh, Mohammad Reza Noori-Daloii, SirousZeinali
      Maple syrup urine disease (MSUD) is a rare inborn error of branched-chain amino acid metabolism. The disease prevalence is higher in populations with high rate of consanguineous marriages such as Iran. Different types of disease causing mutations have been previously reported in BCKDHA, BCKDHB, DBT and DLD genes known to be responsible for MSUD phenotype. In this study, two sets of multiplex polymorphic STR (short tandem repeat) markers linked to the above genes were used to aid in homozygosity mapping in order to find probable pathogenic change(s) in the studied families. The families who showed homozygote haplotype for the BCKDHA gene were subsequently sequenced. Our findings showed that exons 2, 4 and 6 contain most of the mutations which are novel. The changes include two single nucleotide deletion (i.e. c. 143delT and c.702delT), one gross deletion covering the whole exon four c.(375±1_376-1)_(884±1_885-1), two splice site changes (c.1167±1G≥T, c. 288±1G≥A), and one point mutation (c.731G≥A). Computational approaches were used to analyze these two novel mutations in terms of their impact on protein structure. Computational structural modeling indicated that these mutations might affect structural stability and multimeric assembly of branched-chain α-keto acid dehydrogenase complex (BCKDC).


      PubDate: 2016-01-29T22:15:47Z
       
  • Genomic stability during cellular reprogramming: mission impossible'
    • Abstract: Publication date: Available online 20 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mathieu von Joest, Sabela Bua, Han Li
      The generation of induced pluripotent stem cells (iPSCs) from adult somatic cells is one of the most exciting discoveries in recent biomedical research. It holds tremendous potential in drug discovery and regenerative medicine. However, a series of reports highlighting genomic instability in iPSCs raises concerns about their clinical application. Although the mechanisms cause genomic instability during cellular reprogramming are largely unknown, several potential sources have been suggested. This review summarizes current knowledge on this active research field and discusses the latest efforts to alleviate the genomic insults during cellular reprogramming to generate iPSCs with enhanced quality and safety.


      PubDate: 2016-01-24T20:10:29Z
       
  • Polymerase Specific Error Rates and Profiles Identified by Single Molecule
           Sequencing
    • Abstract: Publication date: Available online 19 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Matthew S. Hestand, Jeroen Van Houdt, Francesca Cristofoli, Joris R. Vermeesch
      DNA polymerases have an innate error rate which is polymerase and DNA context specific. Historically the mutational rate and profiles have been measured using a variety of methods, each with their own technical limitations. Here we used the unique properties of single molecule sequencing to evaluate the mutational rate and profiles of six DNA polymerases at the sequence level. In addition to accurately determining mutations in double strands, single molecule sequencing also captures direction specific transversions and transitions through the analysis of heteroduplexes. Not only did the error rates vary, but also the direction specific transitions differed among polymerases.


      PubDate: 2016-01-19T18:44:05Z
       
  • Estimation of the minimum mRNA splicing error rate in vertebrates
    • Abstract: Publication date: Available online 13 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): A. Skandalis
      The majority of protein coding genes in vertebrates contain several introns that are removed by the mRNA splicing machinery. Errors during splicing can generate aberrant transcripts and degrade the transmission of genetic information thus contributing to genomic instability and disease. However, estimating the error rate of constitutive splicing is complicated by the process of alternative splicing which can generate multiple alternative transcripts per locus and is particularly active in humans. In order to estimate the error frequency of constitutive mRNA splicing and avoid bias by alternative splicing we have characterized the frequency of splice variants at three loci, HPRT, POLB, and TRPV1 in multiple tissues of six vertebrate species. Our analysis revealed that the frequency of splice variants varied widely among loci, tissues, and species. However, the lowest observed frequency is quite constant among loci and approximately 0.1% aberrant transcripts per intron. Arguably this reflects the “irreducible” error rate of splicing, which consists primarily of the combination of replication errors by RNA polymerase II in splice consensus sequences and spliceosome errors in correctly pairing exons.


      PubDate: 2016-01-16T18:16:49Z
       
  • XPC deficiency is related to APE1 and OGG1 expression and functions
    • Abstract: Publication date: Available online 16 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Julliane Tamara Araújo de Melo, Ana Rafaela de Souza Timoteo, Tirzah Braz Petta Lajus, Juliana Alves Brandão, Nadja Cristhina de Souza-Pinto, Carlos Frederico Martins Menck, Anna Campalans, J.Pablo Radicella, Alexandre Teixeira Vessoni, Alysson Renato Muotri, Lucymara Fassarella Agnez-Lima
      Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interacts with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.


      PubDate: 2016-01-16T18:16:49Z
       
  • COMPREHENSIVE MOLECULAR TESTING IN PATIENTS WITH HIGH FUNCTIONING AUTISM
           SPECTRUM DISORDER
    • Abstract: Publication date: Available online 6 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Maria Isabel Alvarez-Mora, Rosa Calvo Escalona, Olga Puig Navarro, Irene Madrigal, Ines Quintela, Jorge Amigo, Dei Martinez-Elurbe, Michaela Linder-Lucht, Gemma Aznar Lain, Angel Carracedo, Montserrat Mila, Laia Rodriguez-Revenga
      Autism spectrum disorders (ASD) include a range of complex neurodevelopmental disorders with extreme genetic heterogeneity. Exome and target sequencing studies have shown to be an effective tool for the discovery of new ASD genes. The aim of this study was to design an ASD candidate gene panel that covers 44 of the top ASD candidate genes. As a pilot study we performed comprehensive molecular diagnostic testing, including the study of the FMR1 and FMR2 repeat regions, copy number variant analysis in a collection of 50 Spanish ASD cases and mutation screening using targeted next generation sequencing-based techniques in 44 out of the total cohort. We evaluated and clinically selected our cohort, with most of the cases having high functioning ASD without facial dysmorphic features. The results of the present study allowed the detection of copy number and single nucleotide variants not yet identified. In addition, our results underscore the difficulty of the molecular diagnosis of ASD and confirm its genetic heterogeneity. The information gained from this and other genetic screenings is necessary to unravel the clinical interpretation of novel variants.


      PubDate: 2016-01-08T14:32:13Z
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 783




      PubDate: 2016-01-03T10:26:15Z
       
  • Risky Business: Microhomology-Mediated End Joining
    • Abstract: Publication date: Available online 2 January 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Supriya Sinha, Diana Villarreal, Eun Yong Shim, Sang Eun Lee
      Prevalence of microhomology (MH) at the breakpoint junctions in somatic and germ-line chromosomal rearrangements and in the programed immune receptor rearrangements from cells deficient in classical end joining reveals an enigmatic process called MH-mediated end joining (MMEJ). MMEJ repairs DNA double strand breaks (DSBs) by annealing flanking MH and deleting genetic information at the repair junctions from yeast to humans. Being genetically distinct from canonical DNA DSB pathways, MMEJ is involved with the fusions of eroded/uncapped telomeres as well as with the assembly of chromosome fragments in chromothripsis. In this review article, we will discuss an up-to-date model representing the MMEJ process and the mechanism by which cells regulate MMEJ to limit repair-associated mutagenesis. We will also describe the possible therapeutic gains resulting from the inhibition of MMEJ in recombination deficient cancers. Lastly, we will embark on two contentious issues associated with MMEJ such as the significance of MH at the repair junction to be the hallmark of MMEJ and the relationship of MMEJ to other mechanistically related DSB repair pathways.


      PubDate: 2016-01-03T10:26:15Z
       
 
 
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