Central Role for the XRCC1 BRCT I Domain in Mammalian DNA Single-Strand Break Repair

Taylor, Richard; Thistlethwaite, Angela; Caldecott, Keith W.

doi:10.1128/mcb.22.8.2556-2563.2002

Cited by 160 publications

(148 citation statements)

References 54 publications

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“…These epidemiological results therefore do not provide any conclusive evidence of a direct association of the XRCC1 R399Q SNP with cancer. This conclusion is further supported by a functional study by Taylor et al (2002) using transfected CHO cells deficient in XRCC1 gene product. Cells with the R399Q genotype showed no difference in sensitivity to MMS than cells transfected with Q399R.…”

Section: R399qmentioning

confidence: 56%

“…It is also the site for direct binding to both gapped and nicked DNA, and gapped DNA complexed with POL b (Marintchev et al, 1999). XRCC1 has two BRCT domains, which are weakly conserved motifs first identified in BRCA1, and which mediate protein interactions (Zhang et al, 1998;Taylor et al, 2002;Beernink et al, 2005). BRCT1 is an interactive site for PARP whereas BRCT2 is an interactive binding site for Lig3.…”

Section: Xrcc1 Structurementioning

confidence: 99%

“…The end result is a decreased efficiency of base excision repair. The L360R point mutation occurs within the BRCT1 domain (Figure 4) and inhibits correct folding of the BRCT1 domain (Taylor et al, 2002). The third point mutation, W385D, also occurs in the BRCT1 domain, and allows an increased sensitivity to MMS and other alkylating agents (Taylor et al, 2002), and interferes with PARP1 binding (El-Khamisy et al, 2003).…”

Section: Point Mutations Affect Xrcc1 Functionmentioning

confidence: 99%

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Mouse models of XRCC1 DNA repair polymorphisms and cancer

Ladiges

2006

Oncogene

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DNA damage plays a major role in mutagenesis, carcinogenesis and aging. A gene that is emerging as an essential element in the repair of both damaged bases and single-strand breaks (SSB) is XRCC1. XRCC1 has been shown to have a large number of single-nucleotide polymorphisms (SNPs), several of which are being increasingly studied in cancer epidemiology investigations, in part because of their relative high frequency in the population. Although association trends with specific cancer types have occasionally been shown in a variety of ethnic backgrounds, there are often conflicting reports that weaken any substantial conclusions. The functional significance of these SNPs is still largely unknown. XRCC1 is an excellent prototype to provide a forum for determining how epidemiological cancer association studies with DNA repair gene polymorphisms can be validated or refuted. The focus is on the utilization of in silico data and biochemical studies in cell lines and existing mouse models to help provide a framework for the development of new mutant mouse lines that mimic human polymorphisms. These mouse lines will provide the next generation of mammalian tools for carcinogen exposure studies relevant to human cancer and variations in XRCC1, and provide the basis for investigating groups of genes and polymorphisms in an animal model.

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Section: R399qmentioning

confidence: 56%

Section: Xrcc1 Structurementioning

confidence: 99%

Section: Point Mutations Affect Xrcc1 Functionmentioning

confidence: 99%

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Mouse models of XRCC1 DNA repair polymorphisms and cancer

Ladiges

2006

Oncogene

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“…28 In contrast, an experimental study reported that the Arg399Gln polymorphism does not affect the DNA repair function, suggesting that it has little or no biological impact on cancer susceptibility. 29 Studies on the Arg194Trp polymorphism have produced inconsistent results with respect to the risk of various cancers, even though most published studies have reported a reduced risk of cancer for the 194Trp allele. 30 The inconsistent results of association studies between the polymorphisms and cancer risk may be due to linkage disequilibrium with a determinant variant of the XRCC1 gene.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of XRCC1 gene, alcohol consumption and colorectal cancer

Hong

Lee

Kim

et al. 2005

Intl Journal of Cancer

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To evaluate contribution of polymorphisms of the XRCC1 gene to the risk of colorectal cancer, we conducted a case-control study of 209 colorectal cancer cases and 209 age-and gender-matched controls in the Korean population. We tested the hypothesis by constructing allele combinations with known SNP. Allelic variants of the XRCC1 gene at codons 194, 280 and 399 were analyzed in lymphocyte DNA by PCR-RFLP. We observed an increased risk of colorectal cancer associated with the 399Gln allele. The odds ratio (OR) was 1.61 (95% confidence interval [CI] 1.09-2.39) for the 399Gln allele. When combined allele-specific OR were calculated after estimating frequencies, 3 common allele combinations were found to be associated with an increased risk of colorectal cancer. The OR for the 194Trp-280Arg-399Arg was 1.48 (95% CI 5 1.06-2.07) using 194Arg-280Arg-399Arg as the reference. The OR for the 194Arg-280His-399Arg and the 194Arg-280Arg-399Gln were 1.78 (95% CI 5 1.09-2.89) and 1.78 (95% CI 5 1.23-2.59), respectively. Analysis after controlling for smoking, exercise and dietary habits indicated that alcohol consumption ( 80 g/week) is a significant risk factor of colorectal cancer (OR 5 2.60, 95% CI 5 1. 46-4.62). An increased risk for colorectal cancer was identified in alcohol drinkers with the risky allele combinations. Our results suggest that polymorphisms in the XRCC1 genes may contribute to colorectal cancer susceptibility, and some evidence was obtained of a genetic modification for the relationship between alcohol intake and colorectal cancer. ' 2005 Wiley-Liss, Inc.Key words: polymorphisms; XRCC1; genotype; allele; colorectal cancer; alcohol Colorectal cancer is one of the most commonly diagnosed cancers in North America and Western Europe, 1 and is the fourth most common cause of cancer in South Korea. 2 Inherited deficiencies in DNA repair have been associated with an individual's susceptibility to cancer. 3 Therefore, polymorphisms of DNA repair genes may increase the risk of colorectal cancer.The human XRCC1 gene, one of the DNA repair genes, was identified because of its ability to restore DNA repair activity in a Chinese hamster ovary mutant cell line EM9. 4 The XRCC1 protein is involved in base-excision repair, and interacts with DNA ligase III, DNA polymerase b, poly(ADP-ribose)polymerase (PARP), polynucleotide kinase and AP endonuclease I. 5-8 The base-excision repair pathway is designed to remove non-bulky base adducts, which are produced by methylation, oxidation or reduction by ionizing radiation or oxidative damage. 9,10 Three coding polymorphisms of the DNA repair gene XRCC1 (Arg194Trp, Arg280His and Arg399Gln) have been identified in man, suggesting altered efficiency due to amino acid substitutions. 11,12 Alcohol consumption has been associated with the production of reactive oxygen species, which are known to cause DNA lesions that can be removed by the DNA base-excision repair pathway. 13 Meta-analyses of alcohol consumption in relation to colorectal cancer have reported a small or moderate addit...

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“…There is a large set of data implying the functional importance of the XRCC1-399 polymorphism with the variant Gln allele being associated with a decreased capacity to repair DNA damage and a consequent increased level of DNA damage (Lunn et al, 1999;Duell et al, 2000;Au et al, 2003;Wang et al, 2003;Vodicka et al, 2004). However, contradictory findings have also been reported including a study by (Taylor et al, 2002) who examined the polymorphism in an isogenic cellular background and demonstrated no effect upon the BRCT-mediated functions of XRCC1; instead, it was suggested that potentially functional polymorphisms in neighbouring DNA repair genes may be genetically linked.…”

Section: Base Excision Repairmentioning

confidence: 74%

Advances in the understanding of susceptibility to treatment‐related acute myeloid leukaemia

Seedhouse

Russell

2007

Br J Haematol

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SummaryTreatment-related acute myeloid leukaemia (t-AML) is a devastating complication following exposure to the cytotoxic and genotoxic agents used to treat a primary malignancy. Whilst the incidence of t-AML is rising, it still only occurs in a minority of patients who have received chemotherapy and/or radiotherapy treatment and hence it is important to identify factors that may confer susceptibility to the development of the condition. This paper reviews the literature and discusses the advances and limitations in our understanding of susceptibility factors to t-AML. In particular, it concentrates upon genetic polymorphisms in detoxification genes and in genes belonging to the major DNA repair pathways. This review also considers more novel susceptibility factors, such as those proposed to determine stem cell number. Increased understanding of t-AML susceptibility may enable steps to be taken to prevent its development and increase the effectiveness of treatment of the disease.

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Central Role for the XRCC1 BRCT I Domain in Mammalian DNA Single-Strand Break Repair

Cited by 160 publications

References 54 publications

Mouse models of XRCC1 DNA repair polymorphisms and cancer

Mouse models of XRCC1 DNA repair polymorphisms and cancer

Polymorphisms of XRCC1 gene, alcohol consumption and colorectal cancer

Advances in the understanding of susceptibility to treatment‐related acute myeloid leukaemia

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