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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  [2801 journals]
  • 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
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: October 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 780




      PubDate: 2015-09-27T00:02:53Z
       
  • 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
       
  • Target Sequencing approach intended to discover new mutations in
           Non-Syndromic Intellectual Disability
    • Abstract: Publication date: Available online 10 September 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Anna Morgan, Ilaria Gandin, Chiara Belcaro, Pietro Palumbo, Orazio Palumbo, Elisa Biamino, Valentina Dal Col, Erik Laurini, Sabrina Pricl, Paolo Bosco, Massimo Carella, Giovanni Battista Ferrero, Corrado Romano, Adamo Pio d’Adamo, Flavio Faletra, Diego Vozzi
      The technological improvements over the last years made considerable progresses in the knowledge of the etiology of Intellectual Disability (ID). However at present very little is known about the genetic heterogeneity underlying the Non-Syndromic form of ID (NS-ID). To investigate the genetic basis of NS-ID we analyzed 43 trios and 22 isolated NS-ID patients using a Targeted Sequencing (TS) approach. 71 NS-ID genes have been selected and sequenced in all subjects. We found putative pathogenic mutations in 7 out of 65 patients. The pathogenic role of mutations was evaluated through sequence comparison and structural analysis was performed to predict the effect of alterations in a 3D computational model through molecular dynamics simulations. Additionally, a deep patient clinical re-evaluation has been performed after the molecular results. This approach allowed us to find novel pathogenic mutations with a detection rate close to 11% in our cohort of patients. This result supports the hypothesis that many NS-ID related genes still remain to be discovered and that NS-ID is a more complex phenotype compared to syndromic form, likely caused by a complex and broad interaction between genes alterations and environment factors.


      PubDate: 2015-09-15T02:20:18Z
       
  • 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
       
  • TITLE PAGE (EDI BOARD)
    • Abstract: Publication date: September 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 779




      PubDate: 2015-08-29T01:52:11Z
       
  • Efficient ligase 3-dependent microhomology-mediated end joining repair of
           DNA double-strand breaks in zebrafish embryos
    • Abstract: Publication date: Available online 20 August 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Mu-Dan He, Feng-Hua Zhang, Hua-Lin Wang, Hou-Peng Wang, Zuo-Yan Zhu, Yong-Hua Sun
      DNA double-strand break (DSB) repair is of considerable importance for genomic integrity. Homologous recombination (HR) and non-homologous end joining (NHEJ) are considered as two major mechanistically distinct pathways involved in repairing DSBs. In recent years, another DSB repair pathway, namely, microhomology-mediated end joining (MMEJ), has received increasing attention. MMEJ is generally believed to utilize an alternative mechanism to repair DSBs when NHEJ and other mechanisms fail. In this study, we utilized zebrafish as an in vivo model to study DSB repair and demonstrated that efficient MMEJ repair occurred in the zebrafish genome when DSBs were induced using TALEN (transcription activator-like effector nuclease) or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technologies. The wide existence of MMEJ repair events in zebrafish embryos was further demonstrated via the injection of several in vitro -designed exogenous MMEJ reporters. Interestingly, the inhibition of endogenous ligase 4 activity significantly increased MMEJ frequency, and the inhibition of ligase 3 activity severely decreased MMEJ activity. These results suggest that MMEJ in zebrafish is dependent on ligase 3 but independent of ligase 4. This study will enhance our understanding of the mechanisms of MMEJ in vivo and facilitate inducing desirable mutations via DSB-induced repair.


      PubDate: 2015-08-21T00:40:32Z
       
  • The key role of miR-21-regulated SOD2 in the medium-mediated bystander
           
    • Abstract: Publication date: Available online 14 August 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Wenqian Tian, Xiaoming Yin, Longxiao Wang, Jingdong Wang, Wei Zhu, Jianping Cao, Hongying Yang
      Radiation-induced bystander effect (RIBE) is well accepted in the radiation research field by now, but the underlying molecular mechanisms for better understanding this phenomenon caused by intercellular communication and intracellular signal transduction are still incomplete. Although our previous study has demonstrated an important role of miR-21 of unirradiated bystander cells in RIBEs, the direct evidence for the hypothesis that RIBE is epigenetically regulated is still limited and how miR-21 mediates RIBEs is unknown. Reactive oxygen species (ROS) have been demonstrated to be involved in RIBEs, however, the roles of anti-oxidative stress system of cells in RIBEs are unclear. Using transwell insert co-culture system, we investigated medium-mediated bystander responses in WS1 human fibroblasts after co-culture with HaCaT keratinocytes traversed by α-particles. Results showed that the ROS levels in unirradiated bystander WS1 cells were significantly elevated after 30min of co-culture, and 53BP1 foci, a surrogate marker of DNA damage, were obviously induced after 3h of co-culture. This indicates the occurrence of oxidative stress and DNA damage in bystander WS1 cells after co-culture with irradiated keratinocytes. Furthermore, the expression of miR-21 was increased in bystander WS1 cells, downregulation of miR-21 eliminated the bystander responses, overexpression of miR-21 alone could induce bystander-like oxidative stress and DNA damage in WS1 cells. These data indicate an important mediating role of miR-21 in RIBEs. In addition, MnSOD or SOD2 in WS1 cells was involved in the bystander effects, overexpression of SOD2 abolished the bystander oxidative stress and DNA damage, indicating that SOD2 was critical to the induction of RIBEs. Moreover, we found that miR-21 regulated SOD2, suggesting that miR-21 might mediate bystander responses through its regulation on SOD2. In conclusion, this study revealed a profound role of miR-21-regulated SOD2 of unirradiated WS1 cells in bystander effects induced by α-irradiated HaCaT keratinocytes.


      PubDate: 2015-08-17T06:11:09Z
       
  • DNA sequence context greatly affects the accuracy of bypass across an
           ultraviolet light 6-4 photoproduct in mammalian cells
    • Abstract: Publication date: Available online 13 August 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Pola Shriber, Yael Leitner-Dagan, Nicholas Geacintov, Tamar Paz-Elizur, Zvi Livneh
      Translesion DNA synthesis (TLS) is a DNA damage tolerance mechanism carried out by low-fidelity DNA polymerases that bypass DNA lesions, which overcomes replication stalling. Despite the miscoding nature of most common DNA lesions, several of them are bypassed in mammalian cells in a relatively accurate manner, which plays a key role maintaining a low mutation load. Whereas it is generally agreed that TLS across the major UV and sunlight induced DNA lesion, the cyclobutane pyrimidine dimer (CPD), is accurate, there were conflicting reports on whether the same is true for the thymine-thymine pyrimidine-pyrimidone(6-4) ultraviolet light photoproduct (TT6-4PP), which represents the second most common class of UV lesions. Using a TLS assay system based on gapped plasmids carrying site-specific TT6-4PP lesions in defined sequence contexts we show that the DNA sequence context markedly affected both the extent and accuracy of TLS. The sequence exhibiting higher TLS exhibited also higher error-frequency, caused primarily by semi-targeted mutations, at the nearest nucleotides flanking the lesion. Our results resolve the discrepancy reported on TLS across TT6-4PP, and suggest that TLS is more accurate in human cells than in mouse cells.


      PubDate: 2015-08-17T06:11:09Z
       
  • Reduced gene expression levels after chronic exposure to high
           concentrations of air pollutants
    • Abstract: Publication date: Available online 11 August 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Pavel Rossner, Elena Tulupova, Andrea Rossnerova, Helena Libalova, Katerina Honkova, Hans Gmuender, Anna Pastorkova, Vlasta Svecova, Jan Topinka, Radim J. Sram
      We analyzed the ability of particulate matter (PM) and chemicals adsorbed onto it to induce diverse gene expression profiles in subjects living in two regions of the Czech Republic differing in levels and sources of the air pollution. A total of 312 samples from polluted Ostrava region and 154 control samples from Prague were collected in winter 2009, summer 2009 and winter 2010. The highest concentrations of air pollutants were detected in winter 2010 when the subjects were exposed to: PM of aerodynamic diameter < 2.5μm (PM2.5) (70 vs. 44.9μg/m3); benzo[a]pyrene (9.02 vs. 2.56 ng/m3) and benzene (10.2 vs. 5.5μg/m3) in Ostrava and Prague, respectively. Global gene expression analysis of total RNA extracted from leukocytes was performed using Illumina Expression BeadChips microarrays. The expression of selected genes was verified by quantitative real-time PCR (qRT-PCR). Gene expression profiles differed by locations and seasons. Despite lower concentrations of air pollutants a higher number of differentially expressed genes and affected KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways was found in subjects from Prague. In both locations immune response pathways were affected, in Prague also neurodegenerative diseases-related pathways. Over-representation of the latter pathways was associated with the exposure to PM2.5. The qRT-PCR analysis showed a significant decrease in expression of APEX, ATM, FAS, GSTM1, IL1B and RAD21 in subjects from Ostrava, in a comparison of winter 2010 and summer 2009. In Prague, an increase in gene expression was observed for GADD45A and PTGS2. In conclusion, high concentrations of pollutants in Ostrava were not associated with higher number of differentially expressed genes, affected KEGG pathways and expression levels of selected genes. This observation suggests that chronic exposure to air pollution may result in reduced gene expression response with possible negative health consequences.


      PubDate: 2015-08-12T04:34:38Z
       
  • Positive selection of AS3MT to arsenic water in Andean populations
    • Abstract: Publication date: Available online 29 July 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Christina A. Eichstaedt, Tiago Antao, Alexia Cardona, Luca Pagani, Toomas Kivisild, Maru Mormina
      Arsenic is a carcinogen associated with skin lesions and cardiovascular diseases. The Colla population from the Puna region in Northwest Argentinean is exposed to levels of arsenic in drinking water exceeding the recommended maximum by a factor of 20. Yet, they thrive in this challenging environment since thousands of years and therefore we hypothesise strong selection signatures in genes involved in arsenic metabolism. We analysed genome-wide genotype data for 730,000 loci in 25Collas, considering 24 individuals of the neighbouring Calchaquíes and 24 Wichí from the Gran Chaco region in the Argentine province of Salta as control groups. We identified a strong signal of positive selection in the main arsenic methyltransferase AS3MT gene, which has been previously associated with lower concentrations of the most toxic product of arsenic metabolism monomethylarsonic acid. This study confirms recent studies reporting selection signals in the AS3MT gene albeit using different samples, tests and control populations.


      PubDate: 2015-07-30T21:36:34Z
       
  • Studies of adaptive response and mutation induction in the chronically and
           acutely exposed MCF-10A cells to ionising radiation
    • Abstract: Publication date: Available online 29 July 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Sara Shakeri Manes, Traimate Sangsuwan, Andrzej Wojcik, Siamak Haghdoost
      A phenomenon in which exposure to a low adapting dose of radiation makes cells more resistant to the effects of a subsequent high dose exposure is termed radio-adaptive response. Adaptive response could hypothetically reduce the risk of late adverse effects of chronic or acute radiation exposures in humans. Understanding the underlying mechanisms of such responses are of relevance for radiation protection as well as for the clinical applications of radiation in medicine. However, due to the variability of responses depending on the model system and radiation condition, there is a need to further study under what conditions adaptive response can be induced. In this study, we analyzed if there is a dose rate dependence for the adapting dose, assuming that the adapting dose induces DNA response/repair pathways that are dose rate dependent. MCF-10A cells were exposed to a 50 mGy adapting dose administered acutely (0.40 Gy/min) or chronically (1.4 mGy/h or 4.1 mGy/h) and then irradiated by high acute challenging doses. The endpoints of study include clonogenic cell survival and mutation frequency at X-linked hprt locus. In another series of experiment, cells were exposed to 100 mGy and 1 Gy at different dose rates (acutely and chronically) and then the mutation frequencies were studied. Adaptive response was absent at the level of clonogenic survival and present at the level of mutations only at 1.4 mGy/h administration of adapting dose. Overall, no dose rate effect of the adapting dose was observed at the level of clonogenic survival or mutant frequency. Importantly, no dose rate effect was found comparing acute and chronic exposures.


      PubDate: 2015-07-30T21:36:34Z
       
  • Micronucleus frequency in peripheral blood lymphocytes and frailty status
           in elderly. A lack of association with clinical features
    • Abstract: Publication date: Available online 29 July 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Valdiglesias Vanessa, Bonassi Stefano, Dell'Armi Valentina, Silvana Settanni, Michela Celi, Simona Mastropaolo, Manuela Antocicco, Fini Massimo, Graziano Onder
      Frailty is a condition of vulnerability that carries an increased risk of poor outcome in elder adults. Frail individuals show fatigue, weight loss, muscle weakness, and a reduced physical function, and are known to frequently experience disability, social isolation, and institutionalization. Identifying frail people is a critical step for geriatricians to provide timely geriatric care and, eventually, to improve the quality of life in elderly. The aim of the present study is to investigate the association between frailty status and micronucleus (MN) frequency, a known marker of genomic instability, in a sample of elder adults. Several clinical features were evaluated and their possible association with MN frequency was tested. Criteria proposed by Fried were used to identify frail subjects. Overall, 180 elder adults entered the study, 93 of them (51.7%) frail. No association between MN frequency and frailty status was found under the specific conditions tested in this study(Mean Ratio = 1.06; 95% CI 0.96 - 1.18). The inclusion of MN frequency in the Fried's frailty scale minimally improved the classification of study subjects according to the Multidimensional Prognostic Index (MPI). The presence of genomic instability in the ageing process and in most chronic diseases, demands further investigation on this issue.


      PubDate: 2015-07-30T21:36:34Z
       
  • Defective DNA repair and increased chromatin binding of DNA repair factors
           in Down syndrome fibroblasts
    • Abstract: Publication date: Available online 26 July 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Daniela Necchi, Antonella Pinto, Micol Tillhon, Ilaria Dutto, Melania Maria Serafini, Cristina Lanni, Stefano Govoni, Marco Racchi, Ennio Prosperi
      Down syndrome (DS) is characterized by genetic instability,neurodegeneration, and premature aging. However, the molecular mechanisms leading to thisphenotype are not yet well understood. Here, we report that DS fibroblasts from both fetal and adult donorsshow the presence of oxidative DNA base damage, such asdihydro-8-oxoguanine (8-oxodG), and activation of a DNA damage response (DDR), already during unperturbed growth conditions. DDR with checkpoint activation was indicated by histone H2AX and Chk2 protein phosphorylation, and by increased p53 protein levels. In addition, both fetal and adult DS fibroblasts were more sensitive to oxidative DNA damage induced by potassium bromate, and were defective in the removal of 8-oxodG, as compared with age-matched cells from controlhealthy donors. The analysis of core proteins participating in base excision repair (BER), such as XRCC1 and DNA polymerase, showed that higher amounts of these factors were bound to chromatin in DS than in control cells, even in the absence of DNA damage. These findings occurred in concomitance with increased levels of phosphorylated XRCC1 detected in DS cells. These results indicate thatDS cells exhibit a BERdeficiency, whichis associated with prolonged chromatin association of core BER factors.


      PubDate: 2015-07-27T07:38:17Z
       
  • Effect of Proton and Gamma Irradiation on Human Lung Carcinoma Cells: Gene
           Expression, Cell Cycle, Cell Death, Epithelial-Mesenchymal Transition and
           Cancer-Stem Cell trait as Biological End Points
    • Abstract: Publication date: Available online 26 July 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Himanshi Narang, Amit Kumar, Nagesh Bhat, Badri N. Pandey, Anu Ghosh
      Proton beam therapy is a cutting edge modality over conventional gamma radiotherapy because of its physical dose deposition advantage. However, not much is known about its biological effects vis-a-vis gamma irradiation. Here we investigated the effect of proton- and gamma- irradiation on cell cycle, death, epithelial-mesenchymal transition (EMT) and “stemness” in human non-small cell lung carcinoma cells (A549). Proton beam (3 MeV) was two times more cytotoxic than gamma radiation and induced higher and longer cell cycle arrest. At equivalent doses, numbers of genes responsive to proton irradiation were ten times higher than those responsive to gamma irradiation. At equitoxic doses, the proton-irradiated cells had reduced cell adhesion and migration ability as compared to the gamma-irradiated cells. It was also more effective in reducing population of Cancer Stem Cell (CSC) like cells as revealed by aldehyde dehydrogenase activity and surface phenotyping by CD44+, a CSC marker. These results can have significant implications for proton therapy in the context of suppression of molecular and cellular processes that are fundamental to tumor expansion.


      PubDate: 2015-07-27T07:38:17Z
       
  • Discrimination of Driver and Passenger Mutations in Epidermal Growth
           Factor Receptor in Cancer
    • Abstract: Publication date: Available online 20 July 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): P. Anoosha, Liang-Tsung Huang, R.Sakthivel, D. Karunagaran, M. Michael Gromiha
      Cancer is one of the most life-threatening diseases and mutations in several genes are the vital cause in tumorigenesis. Protein kinases play essential roles in cancer progression and specifically, Epidermal Growth Factor Receptor (EGFR) is an important target for cancer therapy. In this work, we have developed a method to classify Single Amino acid Polymorphisms (SAPs) in EGFR into disease-causing (driver) and neutral (passenger) mutations using both sequence and structure based features of the mutation site by machine learning approaches. We compiled a set of 222 features and selected a set of 21 properties utilizing feature selection methods, for maximizing the prediction performance. In a set of 540 mutants, we obtained an overall classification accuracy of 67.8% with 10 fold cross validation using Support Vector Machines. Further, the mutations have been grouped into four sets based on secondary structure and accessible surface area, which enhanced the overall classification accuracy to 80.2%, 81.9%, 77.9% and 75.1% for helix, strand, coil-buried and coil-exposed mutants, respectively. The method was tested with a blind dataset of 60 mutations, which showed an average accuracy of 85.4%. These accuracy levels are superior to other methods available in the literature for EGFR mutants, with an increase of more than 30%. Moreover, we have screened all possible single amino acid polymorphisms (SAPs) in EGFR and suggested the probable driver and passenger mutations, which would help in the development of mutation specific drugs for cancer treatment.


      PubDate: 2015-07-23T00:29:48Z
       
  • Point mutations in Escherichia coli DNA pol V that confer resistance to
           non-cognate DNA damage also alter protein-protein interactions
    • Abstract: Publication date: Available online 13 July 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Lisa A. Hawver , Mohammad Tehrani , Nicole M. Antczak , Danielle Kania , Stephanie Muser , Jana Sefcikova , Penny J. Beuning
      Y-family DNA polymerases are important for conferring cellular resistance to DNA damaging agents in part due to their specialized ability to copy damaged DNA. The Escherichia coli Y-family DNA polymerases are encoded by the umuDC and dinB genes. UmuC and the cleaved form of UmuD, UmuD′, form UmuD′2C (pol V), which is able to bypass UV photoproducts such as cyclobutane pyrimidine dimers and 6-4 thymine-thymine dimers, whereas DinB is specialized to copy N2-dG adducts, such as N2-furfuryl-dG. To better understand this inherent specificity, we used hydroxylamine to generate a random library of UmuC variants from which we then selected those with the ability to confer survival to nitrofurazone (NFZ), which is believed to cause N2-furfuryl-dG lesions. We tested the ability of three of the selected UmuC variants, A9 V, H282P, and T412I, to bypass N2-furfuryl-dG in vitro, and discovered that pol V containing UmuC A9 V has overall modestly better primer extension activity than WT pol V, whereas the UmuC T412I and UmuC H282P mutations result in much lower primer extension efficiency. Upon further characterization, we found that the ability of the UmuC variant A9 V to render cells UV-mutable is dependent on the proper length of the arm of UmuD′. Cells harboring UmuC variants T412I and H282P show enhanced cleavage of UmuD to form UmuD′, which, together with our other observations, suggests that this may be due to a disruption of a direct interaction between UmuC and UmuD. Thus, we find that protein interactions as well as protein conformation appear to be crucial for resistance to specific types of DNA damage.
      Graphical abstract image

      PubDate: 2015-07-14T23:58:23Z
       
  • Mitochondrial DNA mutations in single human blood cells
    • Abstract: Publication date: Available online 22 June 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yong-Gang Yao , Sachiko Kajigaya , Neal S. Young
      Determination mitochondrial DNA (mtDNA) sequences from extremely small amounts of DNA extracted from tissue of limited amounts and/or degraded samples is frequently employed in medical, forensic, and anthropologic studies. Polymerase chain reaction (PCR) amplification followed by DNA cloning is a routine method, especially to examine heteroplasmy of mtDNA mutations. In this review, we compare the mtDNA mutation patterns detected by three different sequencing strategies. Cloning and sequencing methods that are based on PCR amplification of DNA extracted from either single cells or pooled cells yield a high frequency of mutations, partly due to the artifacts introduced by PCR and/or the DNA cloning process. Direct sequencing of PCR product which has been amplified from DNA in individual cells is able to detect the low levels of mtDNA mutations present within a cell. We further summarize the findings in our recent studies that utilized this single cell method to assay mtDNA mutation patterns in different human blood cells. Our data show that many somatic mutations observed in the end-stage differentiated cells are found in hematopoietic stem cells (HSCs) and progenitors within the CD34+ cell compartment. Accumulation of mtDNA variations in the individual CD34+ cells is affected by both aging and family genetic background. Granulocytes harbor higher numbers of mutations compared with the other cells, such as CD34+ cells and lymphocytes. Serial assessment of mtDNA mutations in a population of single CD34+ cells obtained from the same donor over time suggests stability of some somatic mutations. CD34+ cell clones from a donor marked by specific mtDNA somatic mutations can be found in the recipient after transplantation. The significance of these findings is discussed in terms of the lineage tracing of HSCs, aging effect on accumulation of mtDNA mutations and the usage of mtDNA sequence in forensic identification.


      PubDate: 2015-06-26T13:58:47Z
       
  • Nrf2 facilitates repair of radiation induced DNA damage through homologous
           recombination repair pathway in a ROS independent manner in cancer cells
    • Abstract: Publication date: Available online 22 June 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Sundarraj Jayakumar , Debojyoti Pal , Santosh K. Sandur
      Nrf2 is a redox sensitive transcription factor that is involved in the co-ordinated transcription of genes involved in redox homeostasis. But the role of Nrf2 in DNA repair is not investigated in detail. We have employed A549 and MCF7 cells to study the role of Nrf2 on DNA repair by inhibiting Nrf2 using all-trans retinoic acid (ATRA) or by knock down approach prior to radiation exposure (4Gy). DNA damage and repair analysis was studied by γH2AX foci formation and comet assay. Results suggested that the inhibition of Nrf2 in A549 or MCF7 cells led to significant slowdown in DNA repair as compared to respective radiation controls. The persistence of residual DNA damage even in the presence of free radical scavenger N-acetyl cysteine, suggested that the influence of Nrf2 on DNA repair was not linked to its antioxidant functions. Further, its influence on non-homologous end joining repair pathway was studied by inhibiting both Nrf2 and DNA-PK together. This led to synergistic reduction of survival fraction, indicating that Nrf2 may not be influencing the NHEJ pathway. To investigate the role of homologous recombination repair (HR) pathway, RAD51 foci formation was monitored. There was a significant reduction in the foci formation in cells treated with ATRA or shRNA against Nrf2 as compared to their respective radiation controls. Further, Nrf2 inhibition led to significant reduction in mRNA levels of RAD51. BLAST analysis was also performed on upstream regions of DNA repair genes to identify antioxidant response element and found that many repair genes that are involved in HR pathway may be regulated by Nrf2. Together, these results suggest the involvement of Nrf2 in DNA repair, a hitherto unknown function of Nrf2, putatively through its influence on HR pathway.


      PubDate: 2015-06-26T13:58:47Z
       
  • Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts with
           apurinic/apyrimidinic sites in DNA
    • Abstract: Publication date: Available online 17 June 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Anastasiya A. Kosova , Svetlana N. Khodyreva , Olga I. Lavrik
      Apurinic/apyrimidinic (AP) sites are some of the most frequent DNA damages and the key intermediates of base excision repair. Certain proteins can interact with the deoxyribose of the AP site to form a Schiff base, which can be stabilized by NaBH4 treatment. Several types of DNA containing the AP site were used to trap proteins in human cell extracts by this method. In the case of single-stranded AP DNA and AP DNA duplex with both 5ʹ and 3ʹ dangling ends, the major crosslinking product had apparent molecular mass of 45 kDa. Using peptide mass mapping based on mass spectrometry data, we identified the protein forming this adduct as an isoform of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) called “uracil-DNA glycosylase”. GAPDH is a glycolytic enzyme with many additional putative functions, which include interaction with nucleic acids, different DNA damages and DNA repair enzymes. We investigated interaction of GAPDH purified from HeLa cells and rabbit muscles with different AP DNAs. In spite of the ability to form a Schiff-base intermediate with the deoxyribose of the AP site, GAPDH does not display the AP lyase activity. In addition, along with borohydride-dependent adducts with AP DNA containing single-stranded regions, GAPDH was shown to form also stable borohydride-independent crosslinks with these DNA. GAPDH was proven to crosslink preferentially to AP DNA cleaved via β-elimination mechanism (spontaneously or by AP lyases) as compared to DNA containing the intact AP site. The level of GAPDH–AP DNA adduct formation depends on oxidation of the protein SH-groups; disulfide bond reduction in GAPDH leads to loss of its ability to form adducts with AP DNA. Possible role of formation of stable adducts with AP sites by GAPDH is discussed.
      Graphical abstract image

      PubDate: 2015-06-21T13:07:03Z
       
  • The BAH domain of BAF180 is required for PCNA ubiquitination
    • Abstract: Publication date: Available online 17 June 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Atsuko Niimi , Suzanna R Hopkins , Jessica A Downs , Chikahide Masutani
      Monoubiquitination of proliferating cell nuclear antigen (PCNA) is a critical regulator of Post Replication Repair (PRR). The depletion of BAF180, a unique subunit of the PBAF chromatin remodeling complex in human cells results in reduced PCNA ubiquitination leading to less efficient fork progression following DNA damage, but little is known about the mechanism. Here, we report that the expression of exogenous BAF180 in cells promotes PCNA ubiquitination during S-phase after UV irradiation and it persists for many hours. No correlation was observed between the protein level of ubiquitin-specific protease 1 (USP1) and ubiquitinated PCNA in BAF180 expressing cells. Analysis of cells expressing BAF180 deletion mutants showed that the bromo-adjacent homology (BAH) domains are responsible for this effect. Surprisingly, a deletion construct encoding only the BAH domain region is able to increase the level of ubiquitinated PCNA, even though it is unable to be assembled into the PBAF complex. These results suggest that the ATPase-dependent chromatin remodeling activity of PBAF is not necessary, but instead the BAH domains are sufficient to promote PCNA ubiquitination.


      PubDate: 2015-06-21T13:07:03Z
       
  • HUMAN CIRCULATING PLASMA DNA SIGNIFICANTLY DECREASES WHILE LYMPHOCYTE DNA
           DAMAGE INCREASES UNDER CHRONIC OCCUPATIONAL EXPOSURE TO LOW-DOSE
           GAMMA-NEUTRON AND TRITIUM β-RADIATION
    • Abstract: Publication date: Available online 15 May 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Inna B. Korzeneva , Svetlana V. Kostuyk , Liza S. Ershova , Andrian N. Osipov , Veronika F. Zhuravleva , Galina V. Pankratova , Lev N. Porokhovnik , Natalia N. Veiko
      The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism's cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal β-radiation of tritium (N=176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N=109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1×Ab DNA×TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab DNA and TM values may provide the information about the human organism's cell resistivity to chronic exposure to the low-dose IR and about the development of the adaptive response in the organism that is aimed, firstly, at the effective cfDNA elimination from the blood circulation, and, secondly – at survival of the cells, including the cells with the damaged DNA.


      PubDate: 2015-06-14T11:42:17Z
       
  • A combinatorial role for MutY and Fpg DNA glycosylases in mutation
           avoidance in Mycobacterium smegmatis
    • Abstract: Publication date: Available online 9 June 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Farzanah Hassim , Andrea O. Papadopoulos , Bavesh D. Kana , Bhavna G. Gordhan
      Hydroxyl radical (OH) among reactive oxygen species cause damage to nucleobases with thymine being the most susceptible, whilst in contrast, the singlet oxygen (102) targets only guanine bases. The high GC content of mycobacterial genomes predisposes these organisms to oxidative damage of guanine. The exposure of cellular DNA to OH and one-electron oxidants results in the formation of two main degradation products, the pro-mutagenic 8-oxo-7,8-dihydroguanine (8-oxoGua) and the cytotoxic 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua). These lesions are repaired through the base excision repair (BER) pathway and we previously, demonstrated a combinatorial role for the mycobacterial Endonuclease III (Nth) and the Nei family of DNA glycosylases in mutagenesis. In addition, the Formamidopyrimidine (Fpg/MutM) and MutY DNA glycosylases have also been implicated in mutation avoidance and BER in mycobacteria. In this study, we further investigate the combined role of MutY and the Fpg/Nei DNA glycosylases in Mycobacterium smegmatis and demonstrate that deletion of mutY resulted in enhanced sensitivity to oxidative stress, an effect which was not exacerbated in Δfpg1 Δfpg2 or Δnei1 Δnei2 double mutant backgrounds. However, combinatorial loss of the mutY, fpg1 and fpg2 genes resulted in a significant increase in mutation rates suggesting interplay between these enzymes. Consistent with this, there was a significant increase in C → A mutations with a corresponding change in cell morphology of rifampicin resistant mutants in the Δfpg1 Δfpg2 ΔmutY deletion mutant. In contrast, deletion of mutY together with the nei homologues did not result in any growth/survival defects or changes in mutation rates. Taken together these data indicate that the mycobacterial MutY, in combination with the Fpg DNA N-glycosylases, plays an important role in controlling mutagenesis under oxidative stress.


      PubDate: 2015-06-14T11:42:17Z
       
  • The effect of age at exposure on the inactivating mechanisms and relative
           contributions of key tumor suppressor genes in radiation-induced mouse
           T-cell lymphomas
    • Abstract: Publication date: Available online 10 June 2015
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Masaaki Sunaoshi , Yoshiko Amasaki , Shinobu Hirano-Sakairi , Benjamin J. Blyth , Takamitsu Morioka , Mutsumi Kaminishi , Yi Shang , Mayumi Nishimura , Yoshiya Shimada , Akira Tachibana , Shizuko Kakinuma
      Children are considered more sensitive to radiation-induced cancer than adults, yet any differences in genomic alterations associated with age-at-exposure and their underlying mechanisms remain unclear. We assessed genome-wide DNA copy number and mutation of key tumor suppressor genes in T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2Gy X-rays for 4 consecutive weeks starting during infancy (1 week old), adolescence (4 weeks old) or as young adults (8 weeks old). Although T-cell lymphoma incidence was similar, loss of heterozygosity at Cdkn2a on chromosome 4 and at Ikaros on chromosome 11 was more frequent in the two older groups, while loss at the Pten locus on chromosome 19 was more frequent in the infant-irradiated group. Cdkn2a and Ikaros mutation/loss was a common feature of the young adult–irradiation group, with Ikaros frequently (60%) incurring multiple independent hits (including deletions and mutations) or suffering a single hit predicted to result in a dominant negative protein (such as those lacking exon 4, an isoform we have designated Ik12, which lacks two DNA binding zinc–finger domains). Conversely, Pten mutations were more frequent after early irradiation (60%) than after young adult–irradiation (30%). Homozygous Pten mutations occurred without DNA copy number change after irradiation starting in infancy, suggesting duplication of the mutated allele by chromosome mis-segregation or mitotic recombination. Our findings demonstrate that while deletions on chromosomes 4 and 11 affecting Cdkn2a and Ikaros are a prominent feature of young adult irradiation–induced T-cell lymphoma, tumors arising after irradiation from infancy suffer a second hit in Pten by mis-segregation or recombination. This is the first report showing an influence of age-at-exposure on genomic alterations of tumor suppressor genes and their relative involvement in radiation-induced T-cell lymphoma. These data are important for considering the risks associated with childhood exposure to radiation.


      PubDate: 2015-06-14T11:42:17Z
       
 
 
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