Disease relevance of XRCC1

• Based on the XRCC1 BRCT structure, we have constructed a model for the C-terminal BRCT domain of BRCA1, which frequently is mutated in familial breast and ovarian cancer [1].
• The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia [2].
• These results suggest that amino acid substitution variants of XRCC1 and APE1 may contribute to IR hypersensitivity [3].
• The protective effect of the homozygous variant of XRCC1 Arg399Gln for GERD and BE suggests that base excision repair alterations may occur early in progression to EADC, likely in response to GERD-induced endogenous oxidative or inflammatory DNA damage [4].
• No association between XRCC1 Arg399Gln Dgenotype and breast cancer risk was observed [5].
• JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues [6].

Psychiatry related information on XRCC1

• The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4 [7].
• Polymorphisms of XRCC1 gene, alcohol consumption and colorectal cancer [8].
• The Arg194Trp polymorphism in DNA repair gene XRCC1 and the risk for sporadic late-onset Alzheimer's disease [9].

High impact information on XRCC1

• Moreover, we show that inhibiting XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or preventing CK2 activity using a highly specific inhibitor ablates the rapid repair of cellular DNA single-strand breaks by XRCC1 [10].
• We show that this essential protein kinase phosphorylates the scaffold protein XRCC1 and thereby enables the assembly and activity of DNA single-strand break repair protein complexes in vitro and at sites of chromosomal breakage [10].
• Here, we report that XRCC1 interacts with human polynucleotide kinase in addition to its established interactions with DNA polymerase-beta and DNA ligase III [11].
• Condensin I interacts with the PARP-1-XRCC1 complex and functions in DNA single-strand break repair [12].
• BACKGROUND & AIMS: Adenosine diphosphate ribosyl transferase (ADPRT) and x-ray repair cross-complementing 1 (XRCC1) are major DNA base excision repair proteins acting interactively in repair processes [13].

Chemical compound and disease context of XRCC1

• Carriers of at least one variant allele of XRCC1 Arg194Trp [Arg/Trp and Trp/Trp versus Arg/Arg, odds ratio (OR) = 1.60, 95% confidence interval (CI) = 0.89-2.87] or two variant alleles of XRCC3 241Met/Metmay have an increased risk of breast cancer (Met/Met versus Thr/Thr and Thr/Met, OR = 1.54, 95% CI = 0.94-2.52) [5].
• The inverse association between XRCC1 194Trp and breast cancer risk was attenuated by lower plasma folate status [14].
• The XRCC1 codon 399 Gln allele is associated with adenine to guanine p53 mutations in non-small cell lung cancer [15].
• A reduction in XRCC1 protein levels resulted in decreased SSBR capacity as measured by the comet assay and intracellular NAD(P)H levels, hypersensitivity to the cell killing effects of the DNA damaging agents methyl methanesulfonate (MMS), hydrogen peroxide and ionizing radiation and enhanced formation of micronuclei following exposure to MMS [16].
• The human DNA repair protein XRCC1 was overexpressed as a histidine-tagged polypeptide (denoted XRCC1-His) in Escherichia coli and purified in milligram quantities by affinity chromatography [17].

Biological context of XRCC1

• These data indicate that XRCC1, which has no known catalytic activity, might serve as a scaffold protein during base excision-repair [18].
• We report here that XRCC1, another essential protein involved in the maintenance of genome stability, physically interacts with APE1 and stimulates its enzymatic activities [19].
• The compact XRCC1 structure explains the observed sequence homology between different BRCT motifs and provides a framework for modelling other BRCT domains [1].
• However, the distribution of the XRCC1 Arg399Gln genotypes was significantly different when comparing the t-AML and control groups (chi(2), P =.03) [2].
• XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage [20].

Anatomical context of XRCC1

• Chinese ovary cell lines mutated in XRCC1 have a diminished capacity to initiate the repair of AP sites [19].
• In this study, we provide biochemical data to demonstrate that two preformed XRCC1 protein complexes exist in cycling HeLa cells [21].
• In contrast, DNA ligase III-beta, which does not interact with XRCC1, is only expressed in male meiotic germ cells, suggesting a role for this isoform in meiotic recombination [22].
• Because smoking and obesity are known and suspected pancreas cancer risk factors, and have been associated with DNA damage and oxidative stress in target tissues, we estimated odds ratios (ORs), interaction contrast ratios (ICRs), and 95% confidence intervals for the combined effects of XRCC1 genotype and smoking or body mass index (in kg/m(2)) [23].
• DNA ligase III and the essential protein XRCC1 are present at greatly reduced levels in the xrcc1 mutant CHO cell line EM-C11 [24].

Associations of XRCC1 with chemical compounds

• An acute loss of aprataxin by small interfering RNA renders HeLa cells sensitive to methyl methanesulfonate treatment by a mechanism of shortened half-life of XRCC1 [21].
• A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment [21].
• The copurification of DNA ligase III activity with histidine-tagged XRCC1 suggests that the two proteins are present in the cell as a complex [25].
• Here, we report that XRCC1 interacts physically and functionally with hOGG1, the human DNA glycosylase that initiates the repair by BER of the mutagenic oxidized base 8-oxoguanine [26].
• An XRCC1 protein in which the conserved D-block tryptophan was disrupted by point mutation retained the ability to interact with DNA ligase III-alpha, so this tryptophan must mediate a different, although conserved, role [27].

Physical interactions of XRCC1

• In somatic cells, DNA ligase III alpha forms a stable complex with the DNA repair protein Xrcc1 [28].
• The FHA domain of aprataxin interacts with the C-terminal region of XRCC1 [29].
• We also present data suggesting that poly (ADP-ribose) polymerase can interact with XRCC1 [30].
• XRCC1 not only forms a stable complex with DNA ligase IIIalpha but also interacts with several other DNA repair factors [31].
• PARG also interacts with XRCC1, a DNA repair factor that is recruited by DNA damage-activated PARP-1 [32].

Enzymatic interactions of XRCC1

• An XRCC1 protein in which this 20mer was deleted could not maintain normal levels of DNA ligase III-alpha in transfected rodent cells, a phenotype associated with defective repair [5] [27].

Co-localisations of XRCC1

• XRCC1 co-localizes and physically interacts with PCNA [33].
• This process correlates with the appearance of XRCC1 nuclear foci that colocalize with Rad51 and may thus function in concert with homologous recombination [34].

Regulatory relationships of XRCC1

• XRCC1 in which the weakly conserved C-block was mutated lost the ability to interact with DNA ligase III-alpha [27].
• The N-terminal half of ECT2 (ECT2-N) contains domains related to the cell cycle regulator/checkpoint control proteins including human XRCC1, budding yeast CLB6, and fission yeast Cut5 [35].

Other interactions of XRCC1

• We studied polymorphisms in 3 DNA repair genes: XRCC1, XRCC3, and XPD [2].
• In a multivariate analysis, only XRCC1 R399Q and ERCC1 19007T>C remained significant [36].
• In the univariate analysis, adjusted for age, sex, and Dukes' stage, three polymorphisms were significantly associated with better prognosis: XRCC1 R399Q [hazard ratio (HR), 0.38; 95% CI, 0.17-0.85], XRCC3 T141M (HR, 0.66; 95% CI, 0.45-0.97), and MGMT L84F (HR, 0.14; 95% CI, 0.02-0.99) [36].
• It is noteworthy that 3 of these genes lie in the same region of chromosome 19: genes ERCC1 and ERCC2, which are involved in nucleotide excision repair, and XRCC1, which is involved in the repair of strand breaks [37].
• The interaction between DNA ligase III alpha and XRCC1, which occurs through BRCT motifs in the C-termini of these polypeptides, implicates this isoform of DNA ligase III in the repair of DNA single-strand breaks and BER [38].

Analytical, diagnostic and therapeutic context of XRCC1

• The XRCC1 protein, which is known to bind DNA ligase III, is not absolutely required for the reaction but suppresses strand displacement by DNA polymerase beta, allowing for more efficient ligation after filling of a single nucleotide patch [18].
• In addition, a complex formed between DNA polymerase beta and a double-stranded oligonucleotide containing an incised abasic site was supershifted by XRCC1 in a gel retardation assay [18].
• We show that XRCC1 interacts directly with DNA polymerase beta using far Western blotting, affinity precipitation and yeast two-hybrid analyses [18].
• Affinity chromatography of extract from EM9 cells transfected with pcD2EHX resulted in the copurification of histidine-tagged XRCC1 and DNA ligase III activity [25].
• In the second analysis, DNAs from an independent hybrid panel were digested with restriction enzymes and analyzed by Southern blot hybridization using DNA probes for the three DNA repair genes that are located on human chromosome 19: ERCC1, ERCC2, and X-Ray Repair Cross Complementing 1 (XRCC1) [39].

References