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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  [2817 journals]
  • 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
       
  • Extreme dNTP Pool Changes and Hypermutability in dcd ndk Strains
    • Abstract: Publication date: Available online 29 December 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Lawrence Tse, Tina Manzhu Kang, Jessica Yuan, Danielle Mihora, Elinne Becket, Katarzyna H. Maslowska, Roel M. Schaaper, Jeffrey H. Miller
      Cells lacking deoxycytidine deaminase (DCD) have been shown to have imbalances in the normal dNTP pools that lead to multiple phenotypes, including increased mutagenesis, increased sensitivity to oxidizing agents, and to a number of antibiotics. In particular, there is an increased dCTP pool, often accompanied by a decreased dTTP pool. In the work presented here, we show that double mutants of E. coli lacking both DCD and NDK (nucleoside diphosphate kinase) have even more extreme imbalances of dNTPs than mutants lacking only one or the other of these enzymes. In particular, the dCTP pool rises to very high levels, exceeding even the cellular ATP level by several-fold. This increased level of dCTP, coupled with more modest changes in other dNTPs, results in exceptionally high mutation levels. The high mutation levels are attenuated by the addition of thymidine. The results corroborate the critical importance of controlling DNA precursor levels for promoting genome stability. We also show that the addition of certain exogenous nucleosides can influence replication errors in DCD-proficient strains that are deficient in mismatch repair.


      PubDate: 2015-12-30T10:09:24Z
       
  • Lymphocytes with multiple chromosomal damages in a large cohort of West
           Siberia residents: results of long-term monitoring
    • Abstract: Publication date: Available online 18 December 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Vladimir Druzhinin, Maria Bakanova, Aleksandra Fucic, Tatiana Golovina, Yana Savchenko, Maxim Sinitsky, Valentin Volobayev
      Cells with specific multiple chromosome aberrations, defined as rogue cells (RC) have been described in different populations, predominantly those exposed to radiation. The frequency, etiology and related health risks have still not been elucidated due to their low frequency of occurrences and rarely performed studies. This study reports RC frequency using chromosome aberration (CA) assay in peripheral lymphocytes in the group of 3242 subjects, during a 30-year long follow-up study in a general rural and urban population, children environmentally exposed to radon, occupationally exposed population and lung cancer patients from the Kemerovo region (Siberia, Russian Federation). Results show that the highest RC frequency was present in children environmentally exposed to radon and the lowest in the general urban population. Total frequency of CA did not correlate with frequency of RC. Genotoxic analysis of air and water samples excluded anthropogenic pollution as a possible cause of genome damage and RC frequency. In 85% of RCs, double minutes, observed in a large number of human tumors, were present. Results of CA analysis suggested that radon and its decay products (alpha-emitters) were the leading factors causing RC in subjects exposed to high LET radiation. Thus, RC may be a candidate biomarker for exposure to this type of radiation.


      PubDate: 2015-12-22T08:49:49Z
       
  • “p53 mutation spectrum and its role in prognosis of Oral Cancer
           patients: A study from Gujarat, West India”
    • Abstract: Publication date: Available online 3 December 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ragini D. Singh, Kinjal R. Patel, Prabhudas S. Patel
      Background and aim p53 mutations are critical players in etiopathogenesis of oral cancer. Interestingly, they show differences in terms of type and codon specificity. These differences might be attributed to geographical variations in tobacco use. We aimed to analyze the frequency of p53 mutations in oral cancer patients from Gujarat, India and their effect on clinico-pathological features, local recurrence and survival. Material and methods p53 mutation analysis was performed on 46 paired tissue samples (adjacent normal and primary malignant) using PCR-SSCP and sequencing. Results Sequencing confirmed 51 p53 mutations in 46 paired tissues. Three novel mutations (frameshift deletion in exon 4; G>T transversion at codon 117 in exon 4 and G>A transition at codon 319 in exon 9) were identified. Distinct pattern of p53 mutations was observed: more common C>T transitions and recurring mutation sites at codon 90 and 116 in exon 4. Interestingly, the probability of developing recurrence was higher in small tumors (< 4cms) with p53 mutations and in cases with p53 mutations in both adjacent normal and malignant tissues. A significant low disease free survival and overall survival was observed in cases harboring truncating and transcriptionally non-active mutations. Conclusion We report a very high frequency and a diverse pattern of p53 mutations in cases from this region. Interestingly, three distinct novel mutations in exons 4 and 9 were also observed. Analyzing p53 mutation status in tumor tissues at an early stage could serve as an important prognostic factor.


      PubDate: 2015-12-05T00:10:06Z
       
  • Histone H2AX and the small RNA pathway modulate both non-homologous
           end-joining and homologous recombination in plants
    • Abstract: Publication date: Available online 4 December 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yiping Qi, Yong Zhang, Joshua A. Baller, Daniel F. Voytas
      Using a zinc finger nuclease (ZFN) that creates a site-specific DNA double-strand break (DSB) at the endogenous ADH1 locus, we provide genetic evidence that histone H2AX and DSB-induced small RNAs modulate DNA repair by both non-homologous end-joining (NHEJ) and homologous recombination (HR) in the model plant Arabidopsis thaliana .


      PubDate: 2015-12-05T00:10:06Z
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: December 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 782




      PubDate: 2015-12-05T00:10:06Z
       
  • BRCA1 deficiency increases the sensitivity of ovarian cancer cells to
           auranofin
    • Abstract: Publication date: Available online 28 November 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Deepu Oommen, Dennis Yiannakis, Awadhesh N. Jha
      Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2—related factor 2 (Nrf2) via direct protein–protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.
      Graphical abstract image

      PubDate: 2015-11-29T22:32:34Z
       
  • The crosstalk between α-irradiated Beas-2B cells and its bystander
           U937 cells through MAPK and NF-κB signaling pathways
    • Abstract: Publication date: Available online 15 November 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jiamei Fu, Dexiao Yuan, Linlin Xiao, Wenzhi Tu, Chen Dong, Weili Liu, Chunlin Shao
      Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.


      PubDate: 2015-11-18T21:16:13Z
       
  • AACR Precision Medicine Series: Highlights of the Integrating Clinical
           Genomics and Cancer Therapy Meeting.
    • Abstract: Publication date: Available online 3 November 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Elaine Maggi, Cristina Montagna



      PubDate: 2015-11-06T16:01:37Z
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: November 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 781




      PubDate: 2015-11-01T23:00:32Z
       
  • Oxidative DNA damage is associated with inflammatory response, insulin
           resistance and microvascular complications in type 2 diabetes
    • Abstract: Publication date: Available online 20 October 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Etiane Tatsch, José A.M.De Carvalho, Bruna S. Hausen, Yãnaí S. Bollick, Vanessa D. Torbitz, Thiago Duarte, Rogério Scolari, Marta M.M.F. Duarte, Sílvia W.K. Londero, Rodrigo A. Vaucher, Melissa O. Premaor, Fabio V. Comim, Rafael N. Moresco
      Urinary markers of nucleic acid oxidation may be useful biomarkers in diabetes. It hasbeen demonstrated that T2DM patients have an increased level of oxidative DNA damage; however, it is unclear whether increased DNA damage may be related to a greater degree of inflammation and insulin resistance. Thus, the aim of this present study was to investigate the relation of the impact of oxidative DNA damage, assessed by urinary 8-OHdG, on the levels of inflammatory cytokines, as well as insulin resistance. In addition, we also investigated the diagnostic ability of urinary 8-OHdG in the identification of microvascular complications in T2DM.A case-control study, enrolling 22 healthy controls and 54 subjects with T2DM, was performed to evaluate the relation between oxidative DNA damage and interleukin-6 (IL-6), IL-1,tumor necrosis factor-alpha (TNF-α), IL-10, and Homeostasis Model Assessment (HOMA-IR) index. T2DM patients presented higher urinary 8-OHdG, IL-6, IL-1, TNF-α levels and HOMA-IR, and lower IL-10 levels than control subjects.Moreover, urinary 8-OHdG levels were significantly higher in the group T2DM with microvascular complications when compared to the without complications. The areas under the curve for urinary 8-OHdG and urinary albumin were, respectively, 0.836 (P<0.001) and 0.786 (P= 0.002). Thus, urinary 8-OHdG has a slightly higher ability to discriminate microvascular complications in T2DM compared with urinary albumin. It was also demonstrated that T2DM patients with higher median of urinary 8-OHdG had significantly elevated levels of IL-6, TNF-α and HOMA-IR, and decreased IL-10 levels. Our findings showed that T2DM patients with higher urinary 8-OHdG levels showed a greater inflammatory degree and higher insulin resistance. It is possible to speculate that T2DM patients present a cascade of events as increasing metabolic abnormalities such as insulin resistance and inflammatory activation, as well as increased ROS generation factors that may contribute directly to greater oxidative DNA damage.


      PubDate: 2015-10-28T22:28:04Z
       
  • An altered redox balance and increased genetic instability characterize
           primary fibroblasts derived from Xeroderma pigmentosum group A patients
    • Abstract: Publication date: Available online 23 October 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Eleonora Parlanti, Donatella Pietraforte, Egidio Iorio, Sergio Visentin, Chiara De Nuccio, Andrea Zijno, Mariarosaria D’Errico, Valeria Simonelli, Massimo Sanchez, Paola Fattibene, Mario Falchi, Eugenia Dogliotti
      Xeroderma pigmentosum (XP)-A patients are characterized by increased solar skin carcinogenesis and present also neurodegeneration. XPA deficiency is associated with defective nucleotide excision repair (NER) and increased basal levels of oxidatively induced DNA damage. In this study we search for the origin of increased levels of oxidatively generated DNA lesions in XP-A cell genome and then address the question of whether increased oxidative stress might drive genetic instability. We show that XP-A human primary fibroblasts present increased levels and different types of intracellular reactive oxygen species (ROS) as compared to normal fibroblasts, with O2 • and H2O2 being the major reactive species. Moreover, XP-A cells are characterized by decreased reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios as compared to normal fibroblasts. The significant increase of ROS levels and the alteration of the glutathione redox state following silencing of XPA confirmed the causal relationship between a functional XPA and the control of redox balance. Proton nuclear magnetic resonance (1H NMR) analysis of the metabolic profile revealed a more glycolytic metabolism and higher ATP levels in XP-A than in normal primary fibroblasts. This perturbation of bioenergetics is associated with different morphology and response of mitochondria to targeted toxicants. In line with cancer susceptibility, XP-A primary fibroblasts showed increased spontaneous micronuclei (MN) frequency, a hallmark of cancer risk. The increased MN frequency was not affected by inhibition of ROS to normal levels by N-acetyl-L-cysteine.


      PubDate: 2015-10-28T22:28:04Z
       
  • Unirradiated cells rescue cells exposed to ionizing radiation: activation
           of NF-κB pathway in irradiated cells
    • Abstract: Publication date: Available online 23 October 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): R.K.K. Lam, Wei Han, K.N. Yu
      We studied the involvement of NF-κB pathway activation in the rescue effect in HeLa and NIH/3T3 cells irradiated by α particles. Firstly, upon irradiation by 5 cGy of α particles, for both cell lines, the numbers of 53BP1 foci/cell at 12h post-irradiation were significantly smaller when only 2.5% of the cell population was irradiated as compared to 100% irradiation, which demonstrated the rescue effect. Secondly, we studied the effect of NF-κB on the rescue effect through the use of the NF-κB activation inhibitor BAY-11-7082. Novel experimental setup and procedures were designed to prepare the medium (CM) which had conditioned the bystander cells previously partnered with irradiated cells, to ensure physical separation between rescue and bystander signals. BAY-11-7082 itself did not inflict DNA damages in the cells or have effects on activation of the NF-κB response pathway in the irradiated cells through direct irradiation. The rescue effect was induced in both cell lines by the CM, which was abrogated if BAY-11-7082 was added to the CM. Thirdly, we studied the effect of NF-κB on the rescue effect through staining for phosphorylated NF-κB (p-NF-κB) expression using the anti-NF-κB p65 (phospho S536) antibody. When the fraction of irradiated cells dropped from 100% to 2.5%, the p-NF-κB expression in the cell nuclei of irradiated NIH/3T3 cells increased significantly, while that in the cell nuclei of irradiated HeLa cells also increased although not significantly. Moreover, the p-NF-κB expression in the cell nuclei of irradiated HeLa cells and NIH/3T3 cells treated with CM also increased significantly.


      PubDate: 2015-10-28T22:28:04Z
       
  • Microsatellite instability detected in tumor-related genes in C57BL/6J
           mice with thymic lymphoma induced by N-methyl-N-nitrosourea
    • Abstract: Publication date: December 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 782
      Author(s): Shuangyue Zhang, Xueyun Huo, Zhenkun Li, Xiaohong Li, Wang Tang, Changlong Li, Meng Guo, Xiaoyan Du, Zhenwen Chen
      Microsatellite instability (MSI) has been observed within tumors and found to be closely associated with the degree of malignancy and prognosis in tumors. However, whether MSI in tumor-related genes can be induced by a chemical and whether a connection exists between MSI and tumors remain unclear. In the present study, we detected MSI in the tissues of N-methyl-N-nitrosourea (MNU) treated mice by targeting to 5, 29, 30 microsatellite loci in 3 mismatch repair (MMR) genes, 1 DNA repair gene, and 5 tumor suppressor (TS) genes, respectively. Among 26 mice survived in the MNU-group, 18 (69%) mice presented thymic lymphomas. Moreover, 61% (11/18) of the tumors metastasized to the other organs, including the liver, spleen, and kidney. We examined 104 tissues from MNU-treated mice using the 64 loci, and found 8 MSI events involved 4 loci in 4 tissues types. The MSI incidence in MMR, DNA repair, and TS genes was 67% (2/3), 0% (0/1) and 40% (2/5), respectively. MSI occurrence in tumor and non-tumor tissues was 5.6% (1/18) and 0% (0/8) and that in metastasis and non-metastasis tissues was 7.1% (1/14) and 9.4% (6/64), showing no significant difference. MSI loci in intronic regions of Atm, Msh6 and p21 and MSI in the 3′UTR of Pms2 were detected in MNU-treated mice. Specifically, we found a loss of heterozygosity in intron of Atm (ATM-8) in one metastasis mouse. Four similar events occurred in p21 gene intron (P21-1) of another non-metastasis mouse. Another MSI was a heterozygous mutation existed in an Msh6 allele (MSH6-2) in metastasis mouse. We also found a homozygous 2-bp insertion in the 3′UTR of Pms2 in two non-metastasis mice. These results imply that MNU can induce MSI in MMR and TS genes in C57BL/6J mice. MSI frequency does not seem to be associated with tumorigenesis or metastasis.


      PubDate: 2015-10-28T22:28:04Z
       
  • Gene-specific DNA methylation of DNMT3B and MTHFR and colorectal adenoma
           risk
    • Abstract: Publication date: December 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 782
      Author(s): Vikki Ho, Janet E. Ashbury, Sherryl Taylor, Stephen Vanner, Will D. King
      DNA methyltransferase 3B (DNMT3B) and methylenetetrahydrofolate reductase (MTHFR) are genes which encode enzymes critical to one-carbon metabolism. Polymorphisms in these genes have been implicated in colorectal cancer etiology; however, epigenetic modifications such as gene-specific DNA methylation also affect gene expression. DNA methylation of DNMT3B and MTHFR was quantified in blood leukocytes using Sequenom EpiTYPER® among 272 participants undergoing a screening colonoscopy. DNA methylation was quantified in 66 and 28CpG sites of DNMT3B and MTHFR respectively, and conceptualized using two approaches. First, measures representing average methylation across all CpG sites were created. Second, unsupervised principal component (PC) analysis was used to identify summary variables representing methylation around the transcription start site and in the gene-coding area for both DNMT3B and MTHFR. Logistic regression was used to compare methylation levels between participants diagnosed with colorectal adenoma(s) versus those with a normal colonoscopy via the estimation of odds ratios (ORs) and 95% confidence intervals (95% CIs) for the risk of colorectal adenomas. No association was observed between average DNA methylation of either DNMT3B or MTHFR and colorectal adenoma risk. For DNMT3B, increasing DNA methylation of CpG sites in the gene-coding area was associated with a higher risk of colorectal adenomas (OR=1.34; 95% CI: 1.01–1.79 per SD). This research provides preliminary evidence that methylation of DNMT3B may have functional significance with respect to colorectal adenomas, precursors to the vast majority of colorectal cancers.


      PubDate: 2015-10-28T22:28:04Z
       
  • Single substitution in bacteriophage T4 RNase H alters the ratio between
           its exo- and endonuclease activities
    • Abstract: Publication date: Available online 24 September 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Natalia Kholod, Dmitry Sivogrivov, Oleg Latypov, Sergey Mayorov, Rafail Kuznitsyn, Andrey V. Kajava, Mikhail Shlyapnikov, Igor Granovsky
      The article describes substitutions in bacteriophage T4 RNase H which provide so called das-effect. Phage T4 DNA arrest suppression (das) mutations have been described to be capable of partially suppressing the phage DNA arrest phenotype caused by a dysfunction in genes 46 and/or 47 (also known as Mre11/Rad50 complex). Genetic mapping of das13 (one of the das mutations) has shown it to be in the region of the rnh gene encoding RNase H. Here we report that Das13 mutant of RNase H has substitutions of valine 43 and leucine 242 with isoleucines. To investigate the influence of these mutations on RNase H nuclease properties we have designed a novel in vitro assay that allows us to separate and quantify exo- or endonuclease activities of flap endonuclease. The nuclease assay in vitro showed that V43I substitution increased the ratio between exonuclease/endonuclease activities of RNase H whereas L242I substitution did not affect the nuclease activity of RNase H in vitro. However, both mutations were necessary for the full das effect in vivo. Molecular modelling of the nuclease structure suggests that V43I substitution may lead to disposition of H4 helix, responsible for the interaction with the first base pairs of 5'end of branched DNA. These structural changes may affect unwinding of the first base pairs of gapped or nicked DNA generating a short flap and therefore may stabilize the DNA-enzyme complex. L242I substitution did not affect the structure of RNase H and its role in providing das-effect remains unclear.
      Graphical abstract image

      PubDate: 2015-09-27T00:02:53Z
       
  • Late-occurring chromosome aberrations and global DNA methylation in
           hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon
           (28Si) ions
    • Abstract: Publication date: Available online 12 September 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Kanokporn Noy Rithidech, Louise M. Honikel, Paiboon Reungpathanaphong, Montree Tungjai, Witawat Jangiam, Elbert B. Whorton
      Although myeloid leukemia (ML) is one of the major health concerns from exposure to space radiation, the risk prediction for developing ML is unsatisfactory. To increase the reliability of predicting ML risk, a much improved understanding of space radiation-induced changes in the target cells, i.e. hematopoietic stem/progenitor cells (HSPCs), is important. We focused on the in vivo induction of late-occurring damage in HSPCs of mice exposed to 28Si ions since such damage is associated with radiation-induced genomic instability (a key event of carcinogenesis). We gave adult male CBA/CaJ mice, known to be sensitive to radiation-induced ML, a whole-body exposure (2 fractionated exposures, 15 days apart, that totaled each selected dose, delivered at the dose-rate of 1cGy/min) to various doses of 300MeV/n 28Si ions, i.e. 0 (sham controls), 0.1, 0.25, or 0.5Gy. At 6 months post-irradiation, we collected bone marrow cells from each mouse (five mice per treatment-group) for obtaining the myeloid-lineage of HSPC-derived clones for analyses. We measured the frequencies of late-occurring chromosome aberrations (CAs), using the genome-wide multicolor fluorescence in situ hybridization method. The measurement of CAs was coupled with the characterization of the global DNA methylation patterns, i.e. 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). A dose-dependent increase in the frequencies of CAs was detected (Analysis of Variance or ANOVA, p<0.01), indicating the induction of genomic instability after exposure of mice to 300MeV/n 28Si ions. Slight increases in the levels of 5mC were observed in all treatment groups, as compared to the sham-control level. In contrast, there was a significant reduction in levels of 5hmC (ANOVA, p<0.01). Since these endpoints were evaluated in the same mouse, our data suggested for the first time a link between a reduction in 5hmC and genomic instability in HSPC-derived myeloid colonies of CBA/CaJ mice exposed to 300MeV/n 28Si ions.


      PubDate: 2015-09-15T02:20:18Z
       
  • Tyrosyl-DNA-Phosphodiesterase I (TDP1) participates in the removal and
           repair of stabilized-Top2α cleavage complexes in human cells
    • Abstract: Publication date: Available online 14 September 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Miguel Angel Borda, Micaela Palmitelli, Gustavo Verón, Marcela González-Cid, Marcelo de Campos Nebel
      Tyrosyl-DNA-Phosphodiesterase 1 (TDP1) is a DNA repair enzyme that removes irreversible protein-linked 3' DNA complexes, 3' phosphoglycolates, alkylation damage-induced DNA breaks, and 3' deoxyribose nucleosides. In addition to its extended spectrum of substrates, TDP1 interacts with several DNA damage response factors. To determine whether TDP1 participates in the repair of Topoisomerase II (Top2) induced DNA lesions, we generated TDP1 depleted (TDP1kd) human tumoral cells. We found that TDP1kd cells are hypersensitive to Etoposide (ETO). Moreover, we established in a chromatin context that following treatment with ETO, TDP1kd cells accumulate increased amounts of Top2α cleavage complexes, removing them with an altered kinetics. We also showed that TDP1 depleted cells accumulate increased γH2AX and pS296Chk1 signals following treatment with ETO. Similarly, cytogenetics analyses following Top2 poisoning revealed increased amounts of chromatid and chromosome breaks and exchanges on TDP1kd cells in the presence or not of the DNA-PKcs inhibitor NU7026. However, the levels of sister chromatid exchanges were similar in both TDP1kd and control non-silenced cell lines. This suggests a role of TDP1 in both canonical non-homologous end joining and alternative end joining, but not in the homologous recombination repair pathway. Finally, micronucleus analyses following ETO treatment revealed a higher frequency of micronucleus containing γH2AX signals on TDP1kd cells. Together, our results highlight an active role of TDP1 in the repair of Top2-induced DNA damage and its relevance on the genome stability maintenance in human cells.


      PubDate: 2015-09-15T02:20:18Z
       
  • Evidence for chromosome fragility at the frataxin locus in Friedreich
           ataxia
    • Abstract: Publication date: Available online 30 August 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Daman Kumari, Bruce Hayward, Asako J. Nakamura, William M. Bonner, Karen Usdin
      Friedreich ataxia (FRDA) is a member of the Repeat Expansion Diseases, a group of genetic conditions resulting from an increase/expansion in the size of a specific tandem array. FRDA results from expansion of a GAA/TTC-tract in the first intron of the frataxin gene (FXN). The disease-associated tandem repeats all form secondary structures that are thought to contribute to the propensity of the repeat to expand. The subset of these diseases that result from a CGG/CCG-repeat expansion, such as Fragile X syndrome, also express a folate-sensitive fragile site coincident with the repeat on the affected chromosome. This chromosome fragility involves the generation of chromosome/chromatid gaps or breaks, or the high frequency loss of one or both copies of the affected gene when cells are grown under folate stress or as we showed previously, in the presence of an inhibitor of the ATM checkpoint kinase. Whether Repeat Expansion Disease loci containing different repeats form similar fragile sites was not known. We show here that the region of chromosome 9 that contains the FXN locus is intrinsically prone to breakage in vivo even in control cells. However, like FXS alleles, FRDA alleles show significantly elevated levels of chromosome abnormalities in the presence of an ATM inhibitor, consistent with the formation of a fragile site.
      Graphical abstract image

      PubDate: 2015-09-03T01:52:40Z
       
  • Genetic alterations in periprosthetic soft-tissue masses from patients
           with metal-on-metal hip replacement
    • Abstract: Publication date: Available online 29 August 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Virinder Kaur Sarhadi, Jyrki Parkkinen, Aleksi Reito, Jyrki Nieminen, Noora Porkka, Tiina Wirtanen, Minna Laitinen, Antti Eskelinen, Sakari Knuutila
      Adverse soft tissue reactions in patients with metal-on-metal (MoM) hip replacement are associated with cobalt (Co) and chromium (Cr) particles released from the implant. Exposing the patients to long periods of increased metal ions concentrations resulting from the wear of these implants poses an increased risk of genotoxicity/mutagenicity. A variable proportion of patients develop periprosthetic soft-tissue masses or pseudotumors at the site of the implant. There is a concern that exposure to increased metal ions could increase the risk of cancer. In order to investigate whether the periprosthetic soft-tissue mass harbours any cancer- related genetic alterations, we studied DNA isolated from periprosthetic tissues of 20 patients with MoM hip replacement, for copy number alterations and mutations in hotspot regions of 50 cancer genes using aCGH and amplicon- based next generation sequencing. Our results showed copy number gains at 12q14.3 and 21q21.1in tumour from patient diagnosed with liposarcoma. Copy number alterations in periprosthetic tissues were seen in three other patients, one had a region of gain at 9q24.1 affecting JAK2 and INSL6, and two patients had region of gain at 6p21.1, affecting RUNX2. Mutation analysis showed V1578del mutation in NOTCH1 in two patients. The copy number alterations and mutations seen in periprosthetic soft-tissue masses are earlier reported in either haematological malignancies or in osteoblast related bone dysplasia. The presence of genetic anomalies was associated with longer in-situ time of the implant. Our findings warrant the need of similar studies in larger patient cohorts to evaluate the risk of development of neoplastic alterations in periprosthetic tissues of patients with MoM hip replacement.


      PubDate: 2015-09-03T01:52:40Z
       
  • A new practical guide to the Luria-Delbrück protocol
    • Abstract: Publication date: Available online 28 August 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Qi Zheng
      Since 2000 several review papers have been published about the analysis of experimental data obtained using the Luria-Delbrück protocol. These timely papers cleared much of the confusion surrounding various methods for estimating or comparing mutation rates. As a result, today the fluctuation test is more widely applied with much improved accuracy. The present paper provides guidelines on a few remaining problems that continue to baffle mutation researchers. Among the issues addressed are incomplete plating, relative fitness, and comparison of experiments where average final cell population sizes differ. It also offers a fresh view on the estimation methods that are based on the sample median.


      PubDate: 2015-08-29T01:52:11Z
       
 
 
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