Molecular genetic analysis of the polymorphism of repair genes of double-strand breaks DNA strand breaks and repair «inconsistencies» DNA in workers of hazardous industries

2019 ◽  
Vol 1 (7) ◽  
pp. 395-399
Author(s):  
Тatyana A. Andrushchenko ◽  
Sergey V. Goncharov ◽  
Viktor Е. Dosenko ◽  
Konstantin E. Ischeikin
Keyword(s):  
Dna Repair ◽  
Respiratory System ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Double Strand Breaks ◽  
Dna Repair Genes ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Increased Risk ◽  
Repair Genes

Introduction. Presents results of a study of polymorphisms of repair genes of double-strand breaks DNA breaks: XRCC7 (rs7003908), ATM (rs664677), repair «inconsistencies» DNA MLH1 (rs1799977) in miners and workers of asbestos factories professionally due to broncho-pulmonary pathology. T e aim of the study was to research the frequency distribution of genotypes of DNA repair genes: XRCC7 (rs7003908), ATM (rs664677) and MLH1 (rs1799977) in workers of harmful and dangerous industries to identify markers of increased risk of bronchopulmonary pathology. Materials and methods. In 90 people with bronchopulmonary pathology and 124 respondents who worked in the same working conditions but had no history of diseases of the respiratory system, polymerase chain reaction in real time studied the polymorphism of DNA repair genes: XRCC7 (rs7003908), ATM (rs664677) and MLH1 (rs1799977). Results. It was found that the genotypes ATM×T/T and MLH1×A/G are associated with the risk of bronchopulmonary pathology. Genotypes that contribute to resistance to the development of respiratory system pathology were also established: ATM×A/A, ATM× A/T and MLH1×A/A. Conclusion. Genotypes associated with the risk of bronchopulmonary pathology were established: ATM×T/T (р≤0.01, χ2=6.61; OR=2.48; 95%CI: 1.16–5.31) and MLH1×A/G (p≤0.002, χ2=9.00; OR=2.32; 95%CI: 1.29–4.21). Also determined the genotypes that contribute to resistance to the development of diseases of the respiratory system: ATM×a/A (OR=0,83; 95%CI: 0,45–1,54), ATM×A/T (OR=0,67; 95% CI: 0,38–1,21) and MLH1× a/A (р≤0,003, χ2=8,73; OR=0,43; 95% CI: 0,24–0,79).

scholarly journals ALLELIC POLYMORPHISMS OF DNA REPAIR GENES AND THEIR INFLUENCE ON THE FORMATION OF RESISTANCE TO THE DEVELOPMENT OF BRONCHOPULMONARY PATHOLOGY UNDER THE ACTION OF INDUSTRIAL AEROSOLS

2019 ◽  
Vol 72 (5) ◽  
pp. 784-789
Author(s):  
Tetyana A. Andrushchenko ◽  
Sergiy V. Goncharov ◽  
Victor E. Dosenko ◽  
Konstantin E. Ishhejkin
Keyword(s):  
Polymerase Chain Reaction ◽  
Dna Repair ◽  
Respiratory System ◽  
Preventive Measures ◽  
Dna Repair Genes ◽  
Chain Reaction ◽  
Asbestos Cement ◽  
Increased Risk ◽  
Polymerase Chain ◽  
Repair Genes

Introduction: The frequency of alleles and genotypes of DNA repair genes in people working due to the influence of industrial aerosols (miners and workers of asbestos-cement plants (n = 215)) was studied. The aim of the work was to identify allelic polymorphisms affecting the formation of resistance or leading to an increased risk of developing bronchopulmonary pathology. Materials and methods: In 90 patients with bronchopulmonary pathology and 125 persons working under the same conditions but without respiratory system diseases, the polymerase chain reaction in real time was determined by the polymorphisms of DNA repair genes: XPD (rs13181, rs799793), ERCC1 (rs11615), XRCC1 ( rs25487) and XRCC3 (rs861539), ATM (rs664677), XRCC7 (rs7003908) and MLH1 (rs1799977). Results: In the course of this study the alleles and genotypes contributing to resistance to the development of respiratory system pathologies were determined: XRCC1•G/A (rs25487) (OR=0.57; 95% CI: 0.32-1.02; P≤0.040; χ²=4.14); MLH1•A (rs1799977) (OR=0.62; 95% CI: 0.40-0.96; P≤0.020; χ²=5.06); MLH1•A/A (rs1799977) (OR=0.43; 95% CI: 0.24-0.79; P≤0.003; χ²=8.73). Also, we established the alleles and genotypes associated with the risk of developing bronchopulmonary pathology: XPD•C/C (rs13181) (OR=2.20, 95% CI: 1.02-4.77; P≤0.020; χ²=4.85); XRCC1•A/A (rs25487) (OR=3.37; 95 % CI: 1.22-9.63; P≤0.008; χ²=6.94); ATM•T/T (rs664677) (OR=2.48; 95% CI: 1.16-5.31; Р≤0.010; χ²=6.61); MLH1•G (rs1799977) (OR=1.61; 95% CI: 1.04-2.49; P≤0.020; χ²=5.06); MLH1•A/G (rs1799977) (OR=2.32; 95% CI: 1.29-4.21; P≤0.002; χ²=9.01). Conclusions: The results indicate the influence of allelic polymorphisms of DNA repair genes on the formation of resistance to the development of bronchopulmonary pathology under the action of industrial aerosols and open up prospects for the development of modern preventive measures.

scholarly journals Effects of Mutations in DNA Repair Genes on Formation of Ribosomal DNA Circles and Life Span inSaccharomyces cerevisiae

1999 ◽  
Vol 19 (5) ◽  
pp. 3848-3856 ◽  
Author(s):  
Peter U. Park ◽  
Pierre-Antoine Defossez ◽  
Leonard Guarente
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Life Span ◽  
Ribosomal Dna ◽  
Initial Step ◽  
Double Strand Breaks ◽  
Strand Breaks ◽  
Mother Cells ◽  
Mutant Cells ◽  
Repair Genes

ABSTRACT A cause of aging in Saccharomyces cerevisiae is the accumulation of extrachromosomal ribosomal DNA circles (ERCs). Introduction of an ERC into young mother cells shortens life span and accelerates the onset of age-associated sterility. It is important to understand the process by which ERCs are generated. Here, we demonstrate that homologous recombination is necessary for ERC formation. rad52 mutant cells, defective in DNA repair through homologous recombination, do not accumulate ERCs with age, and mutations in other genes of the RAD52 class have varying effects on ERC formation. rad52 mutation leads to a progressive delocalization of Sir3p from telomeres to other nuclear sites with age and, surprisingly, shortens life span. We speculate that spontaneous DNA damage, perhaps double-strand breaks, causes lethality in mutants of the RAD52 class and may be an initial step of aging in wild-type cells.

Increased Frequency of Polymorphisms in XRCC3 and OGG1 Genes in Patients with MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3445-3445
Author(s):  
Hadrian Szpurka ◽  
Abdo Haddad ◽  
Soumit Basu ◽  
Mikkael Sekeres ◽  
Jaroslaw P. Maciejewski
Keyword(s):  
Dna Repair ◽  
Genetic Factors ◽  
Dose Effect ◽  
Dna Repair Genes ◽  
Genetic Traits ◽  
Increased Risk ◽  
Disease Predisposition ◽  
Radiation Induced ◽  
Or Gene ◽  
Repair Genes

Abstract The effects of genetic factors on susceptibility to MDS are not well understood. The predisposition may be a result of complex genetic traits, various theories can explain how inherited genic sequence alterations could result in a higher susceptibility to this disease. In theory, genes involved in the metabolism of genotoxic chemicals, DNA repair genes and immunogenetic factors could all play a role. Possibly, the predisposition can be multifactorial and overall risk for MDS modified by acute or cumulative effects of environmental exposures. Alterations/variants of genes involved in MDS may result from mutations, which due to LOH or “gene dose effect” could lead to functional consequences. In addition SNPs, may be present in a variety of genes and by modifying their function result in a disease predisposition. For example, genes coding for enzymes involved in the metabolism or detoxification of cancirogens may show polymorphisms associated with low functional capacity. Based on previous reports, we have selected 4 genes for which specific SNPs have been implicated in increased risk of malignancies. Genes involved in DNA repair constitute rational targets of analysis in MDS as their dysfunction could explain increased frequency of chromosomal aberrations characteristic for this disease. For example, OGG1, XRCC1 and XRCC3 have been implicated in sensitivity to DNA damage following radiation and their variants may increase radiation-induced risk of malignancies. The NQO1 variant (involved in the protection of DNA from oxidative damage) was found to be associated with secondary AML (sAML). We have studied the frequency of homo- and heterozygous SNPs of these genes in MDS to determine whether they constitute genetic factors predisposing to MDS. Experimental cohort included 62 patients with MDS (35 RA/RS, 19 RAEB/t and 8 CMML). An allele specific Taqman PCR assay was designed to distinguish between SNPs in OGG1 (S326C), XRCC1 (R399Q), XRCC3 (T241M) and NQO1 (P187S). When XRCC3 was analyzed, C/T and T/T genotype was found in 75% of MDS patients (vs. 47% in controls; N=175; p<.001). Interestingly, 3 out of 4 patients with sAML were homozygous for the T/T genotype. When patients with RCMD were separately analyzed, 8/10 patients showed at least one allele with XRCC1 G→A SNP (80% vs. 47% p<.001). Based on historically established large cohorts of controls, we did not find an increased frequency of homo- or heterozygous variants of NQO1, XRCC1 or OGG1 in the MDS group as a whole. However, 9/12 (80%) patients with RAEB-2 showed at least one allele with C→G SNP (vs. 29% in controls, N=31). Interestingly, we have found 4 MDS (6%) patients homozygous for OGG1 variant (G/G) that has not been described in healthy controls. Three of these 4 patients had MDS/MPL overlap and one showed evolution to AML. In general, we did not find any correlation between the presence of the gene variants tested and evolution of karyotypic abnormalities. Although we have analyzed only 4 selected DNA repair genes in MDS, our findings suggest that genetically-determined decreased function of these genes may constitute a predisposition factor for the development of this disease. Increased frequency of XRCC3 C/T SNP and presence of patients homozygous for OGG1 G/G may represent examples of such susceptibility. More comprehensive analysis may reveal further polymorphisms that could alone or in context of other defects explain occurrence of MDS.

A Polymorphism Study on Detoxification and DNA Repair Genes in 700 MDS Patients Demonstrates An Association Between Genotype and An Aberrant Karyotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2690-2690
Author(s):  
C. Seedhouse ◽  
Stephanie Fischer ◽  
Christina Ganster ◽  
Christa Fonatsch ◽  
Peter Valent ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genetic Stability ◽  
Genetic Instability ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Xrcc3 Thr241met ◽  
Repair Genes

Abstract The maintenance of genetic stability within haematopoietic stem cells is essential for normal haematopoiesis and this is emphasised by the association of leukemias and myelodysplastic syndromes (MDS) with genetic instability. DNA is normally protected from damage via a number of complex pathways including detoxification and DNA repair pathways. Inefficient processing of DNA damage may result in an increased susceptibility to leukemia and MDS. Genetic polymorphisms exist in many genes within the DNA damage processing pathways, some of which affect the cells ability to maintain genetic stability. We have studied polymorphisms in the homologous DNA repair genes RAD51 (RAD51-g135c) and XRCC3 (XRCC3-Thr241Met) and the detoxification gene GSTM1 (deletion polymorphism) in more 700 MDS samples. The GSTM1 polymorphism was studied using PCR, and the RAD51 and XRCC3 genotypes were assayed simultaneously using a SNaPshot technique. The genotype distributions of RAD51-g135c and GSTM1 did not differ significantly from those reported in the literature. However the distribution of the XRCC3-Thr241Met polymorphism was found to be significantly different, with an over-representation of the variant Met allele, when compared to previously published frequencies in control populations1 (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.3–2.6, p<0.001). Whilst the presence of a single polymorphic variant may display only a subtle effect, polymorphic variants of more than one gene involved in the same pathway are likely to be biologically important with respect to the cellular ability to maintain genetic integrity and hence may play a role in MDS pathogenesis. RAD51, XRCC3 and GSTM1 genotypes were therefore studied in combined analyses. Similar to studies in AML1, the double DNA repair gene variant (RAD51–135c/XRCC3–241) was over-represented in MDS compared to a control population (OR 3.8; 95% CI 1.6–9.3, p=0.002). The triple variant genotype (RAD51–135c/XRCC3–241Met/GSTM1-null) was associated with a further increased risk of MDS (OR 13.5; 95% CI 1.8–102.8, p=0.01). More detailed analysis was undertaken to compare the polymorphic distributions in MDS with aberrant karyotypes. When the single genes were assessed, the GSTM1 null genotype was the only one to be over-represented in MDS with an aberrant karyotype compared to MDS with a normal karyotype (OR 1.6; 95% CI 1.05–2.5). Interestingly, when analysing the genotypes with respect to the XRCC3/RAD51 combined genotypes the presence of homozygous wild type alleles of one DNA repair gene matched with the presence of a variant allele of the other DNA repair gene is significantly protective against karyotypic abnormalities when compared to the double WT patients (OR 0.29; 95% CI 0.29–0.78; p=0.003). Collectively these results suggest that polymorphisms in genes which process DNA damage play a significant role in MDS pathogenesis and may also contribute to genetic instability in MDS.

scholarly journals Implication of polymorphisms in DNA repair genes with an increased risk of hepatocellular carcinoma

2014 ◽  
Vol 13 (2) ◽  
pp. 3812-3818 ◽  
Author(s):  
J.S. Wu ◽  
Y.P. Chen ◽  
L.C. Wang ◽  
Y.J. Yang ◽  
C.W. Deng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Increased Risk ◽  
Repair Genes

scholarly journals Polymorphism of DNA repair genes in bronchopulmonary pathology in workers of harmful and dangerous industries

2018 ◽  
Vol 81 (1) ◽  
pp. 49-56
Author(s):  
T.A. Andruschenko ◽  
S.V. Honcharov ◽  
L.V. Dolinchuk ◽  
V.Ye. Dosenko
Keyword(s):  
Dna Repair ◽  
Molecular Genetic ◽  
Dna Repair Genes ◽  
Risk Markers ◽  
Individual Sensitivity ◽  
Asbestos Cement ◽  
Polymerase Chain ◽  
The Individual ◽  
Mutagenic Effects ◽  
Repair Genes

Introduction. Polymorphism of DNA repair genes is actively studied in the formation of the individual sensitivity of the genome to damaging mutagenic effects. Objective of the work. To study the distribution of frequencies of alleles and genotypes of DNA repair genes: XPD (rs13181, rs799793) and ERCC1 (rs11615) in workers of asbestos-cement plants and miners to identify risk markers for bronchopulmonary pathology. Material and methods. The study included workers of asbestos-cement plants and miners (n=214). Real-time polymerase chain reaction was used to determine genotypes of XPD (rs13181, rs799793) and ERCC1 (rs11615) genes. Results. The study determined alleles and genotypes associated with the risk of developing bronchopulmonary pathology: - in the population of workers of asbestos-cement plants: XPD*Asn/Asn (rs799793), (p<0.01; χ2=6.62; OR=2,20; 95 %CI: 1,75–2,77); - in the population of miners: XPD*C (rs13181), (p<0.02; χ2=4,99; OR=1,88; 95 %CI: 1,04–3,40); XPD*CC (rs13181), (p<0,003; χ2=8.61; OR=4,29; 95 %CI: 1,41–13,37). The study also detected allele XPD*A (rs13181), which in the population of miners proved to be a marker of resistance to bronchopulmonary pathology (p<0,02; χ2=4.99; OR=0,53; 95 %CI: 0,29–0,96). Conclusions. The study has identified alleles and genotypes associated with the risk of developing bronchopulmonary pathology in the population of workers in harmful and dangerous production facilities of Ukraine. The study has determined the genotype and allele that can be used as biomarkers of resistance to the pathology of the respiratory system. Key words: molecular-genetic markers, XPD and ERCC1, bronchopulmonary pathology.

Genetic polymorphisms in DNA repair genes XRCC1 and 3 are associated with increased risk of breast cancer in Bangladeshi population

2020 ◽  
Vol 182 (3) ◽  
pp. 739-750
Author(s):  
Nupur Rani Howlader ◽  
Md. Mostafizur Rahman ◽  
Md. Amir Hossain ◽  
Razia Sultana ◽  
Syed Mozammel Hossain ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Genetic Polymorphisms ◽  
Dna Repair Genes ◽  
Increased Risk ◽  
Bangladeshi Population ◽  
Repair Genes

scholarly journals Association of DNA repair genes polymorphisms and mutations with increased risk of head and neck cancer: a review

2017 ◽  
Vol 34 (12) ◽  
Author(s):  
Agata Dylawerska ◽  
Wojciech Barczak ◽  
Anna Wegner ◽  
Wojciech Golusinski ◽  
Wiktoria Maria Suchorska
Keyword(s):  
Dna Repair ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Dna Repair Genes ◽  
Increased Risk ◽  
Repair Genes

scholarly journals Pathogenic Germline Mutations in DNA Repair Genes in Combination With Cancer Treatment Exposures and Risk of Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer

2020 ◽  
Vol 38 (24) ◽  
pp. 2728-2740 ◽  
Author(s):  
Na Qin ◽  
Zhaoming Wang ◽  
Qi Liu ◽  
Nan Song ◽  
Carmen L. Wilson ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Treatment ◽  
Childhood Cancer ◽  
Excision Repair ◽  
Statistical Significance ◽  
Germline Mutations ◽  
Cancer Surveillance ◽  
Dna Repair Genes ◽  
Increased Risk ◽  
Repair Genes

PURPOSE To investigate cancer treatment plus pathogenic germline mutations (PGMs) in DNA repair genes (DRGs) for identification of childhood cancer survivors at increased risk of subsequent neoplasms (SNs). METHODS Whole-genome sequencing was performed on blood-derived DNA from survivors in the St Jude Lifetime Cohort. PGMs were evaluated in 127 genes from 6 major DNA repair pathways. Cumulative doses of chemotherapy and body region–specific radiotherapy (RT) were abstracted from medical records. Relative rates (RRs) and 95% CIs of SNs by mutation status were estimated using multivariable piecewise exponential models. RESULTS Of 4,402 survivors, 495 (11.2%) developed 1,269 SNs. We identified 538 PGMs in 98 DRGs ( POLG, MUTYH, ERCC2, and BRCA2, among others) in 508 (11.5%) survivors. Mutations in homologous recombination (HR) genes were significantly associated with an increased rate of subsequent female breast cancer (RR, 3.7; 95% CI, 1.8 to 7.7), especially among survivors with chest RT ≥ 20 Gy (RR, 4.4; 95% CI, 1.6 to 12.4), or with a cumulative dose of anthracyclines in the second or third tertile (RR, 4.4; 95% CI, 1.7 to 11.4). Mutations in HR genes were also associated with an increased rate of subsequent sarcoma among those who received alkylating agent doses in the third tertile (RR, 14.9; 95% CI, 4.0 to 38.0). Mutations in nucleotide excision repair genes were associated with subsequent thyroid cancer for those treated with neck RT ≥ 30 Gy (RR, 12.9; 95% CI, 1.6 to 46.6) with marginal statistical significance. CONCLUSION Our study provides novel insights regarding the contribution of genetics, in combination with known treatment-related risks, for the development of SNs. These findings have the potential to facilitate identification of high-risk survivors who may benefit from genetic counseling and/or testing of DRGs, which may further inform personalized cancer surveillance and prevention strategies.

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