Disease relevance of XRCC3

• The C allele (position 18067) of the XRCC3 gene was weakly but significantly associated with colorectal cancer (odds ratio 1.52, 95% confidence interval 1.04-2.22, P=0.03) [1].
• Defects in vertebrate XRCC3 result in elevated levels of spontaneous and DNA damage-induced chromosomal abnormalities, as well as increased sensitivity to DNA damaging agents [2].
• The Thr/Thr genotype in XRCC3 codon 241 correlated with increased risk of subcutaneous fibrosis as well as telangiectasia [3].
• RESULTS: A significant increased risk of second neoplasms (all sites combined, as well as for UADT sites and for head and neck squamous cell cancers) was observed among XRCC3 241Met allele homozygotes (HR 2.65-3.44, P < .02) [4].
• 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].

High impact information on XRCC3

• XRCC3 possesses a limited sequence similarity to Rad51 and interacts with it [6].
• Using a novel fluorescence-based assay, we demonstrate here that error-free homology-directed repair of DNA double-strand breaks is decreased 25-fold in an XRCC3-deficient hamster cell line and can be restored to wild-type levels through XRCC3 expression [6].
• XRCC3 promotes homology-directed repair of DNA damage in mammalian cells [6].
• XRCC3 mutation causes severe chromosome instability [7].
• We find that XRCC3 mutant cells display radically altered HR product spectra, with increased gene conversion tract lengths, increased frequencies of discontinuous tracts, and frequent local rearrangements associated with HR [7].

Chemical compound and disease context of XRCC3

• Cancer occurrence was strongly associated with the XRCC3 Met/Met polymorphic variant (OR = 9.45; (95% CI 8.77-11.65)), whereas Thr/Thr and Thr/Met variants were associated with significant reduction in colorectal cancer risk (OR = 0.16; 95% CI 0-0.26 and OR = 0.26; 95% CI 0.25-0.27, respectively) [8].
• XRCC1, XRCC3, and XPD Polymorphisms as Modifiers of the Effect of Smoking and Alcohol on Colorectal Adenoma Risk [9].

Biological context of XRCC3

• XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages [10].
• We studied polymorphisms in 3 DNA repair genes: XRCC1, XRCC3, and XPD [11].
• In the homologous recombination (HR) pathway, genotype frequencies differed between cases and controls for two polymorphisms in XRCC3; T241M (P=0.015) and IVS5 A>G at nt 17893 (P=0.008) [12].
• For XRCC3, we found evidence for four common haplotypes and four rarer ones that appear to have arisen by recombination [12].
• The XRCC2, XRCC3, and XRCC5 mutants also showed normal induction kinetics [13].

Anatomical context of XRCC3

• The human XRCC2 and XRCC3 genes, which functionally complement irs1 and irs1SF, respectively, were previously mapped in somatic cell hybrids [10].
• The level of XRCC3 protein was also sharply reduced in Rad51C-depleted HeLa cells, suggesting that XRCC3 is dependent for its stability upon heterodimerization with Rad51C [14].
• We evaluate here whether RAD51 and its paralogues XRCC2 and XRCC3 act via a common pathway for sensitivity to genotoxic stress, centrosome fragmentation and chromosome stability [15].
• We established mutant cell lines complemented with either wild-type or variant cDNAs of three human genes, RAD51, XRCC2, and XRCC3, and assessed their sensitivity to cisplatin and mitomycin C [16].
• Genotypes were determined in tumour tissue and distant mucosa samples by PCR RFLP with the NciI restriction enzyme for XRCC1 and NcoI for XRCC3 [8].

Associations of XRCC3 with chemical compounds

• Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization [17].
• A decreased risk of oral clefts was found for XRCC3 (OR = 0.62; CI = 0.39-0.99) and hOGG1 (326 Cys/Cys, OR = 0.22; CI = 0.06-0.78) [18].
• We found no evidence of associations between the XRCC1 codon 194 Arg/Trp or Trp/Trp genotypes and the XRCC3 codon 241 Thr/Met or Met/Met genotypes [19].
• CONCLUSION: XRCC3 241 MetMet is an independent determinant of favorable survival in NSCLC patients treated with cisplatin/gemcitabine [20].
• We examined the role of a common polymorphism in the XRCC3 gene (codon 241: threonine to methionine change) and bladder cancer risk [21].

Physical interactions of XRCC3

• For example, Rad51B expression enhances the binding of Rad51C to XRCC3 and to HsRad51D, and Rad51C expression allows the indirect interaction of Rad51B with Rad51D [22].
• XRCC3 apparently interacted with the N-acetyltransferase type 2 (NAT-2) genotype [23].
• FANCG was found to interact with XRCC3, and this interaction was disrupted by the FA-G patient derived mutation L71P [24].

Regulatory relationships of XRCC3

• XRCC3 depletion induces spontaneous DNA breaks and p53-dependent cell death [25].

Other interactions of XRCC3

• In this study, we show that human RAD51 interacts with RAD51C-XRCC3 or RAD51B-C-D-XRCC2 [26].
• Complex formation by the human RAD51C and XRCC3 recombination repair proteins [27].
• The distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes were not significantly different in patients and controls [11].
• These observations suggest that GSTT1 null and XRCC3 T(241)M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent [28].
• Polymorphic microsatellites in three DNA repair genes, XRCC1, XRCC3 and XRCC5, were analyzed for possible linkage to cancer status or clinical radiosensitivity [29].

Analytical, diagnostic and therapeutic context of XRCC3

• We tested in vitro complex formation by wild-type and mutant XRCC3 with His6-tagged Rad51C upon co-expression in bacteria, nickel-affinity purification, and Western blotting [30].
• Using immunoprecipitation and gel filtration analyses, we found that Holliday junction resolvase activity associated tightly and co-eluted with the 80-kDa RAD51C-XRCC3 complex [31].
• Odds ratios (ORs) were significantly greater than 1 only for the XRCC3 (exon 7) variant, and they were consistent across the 2 control groups [23].
• Polymorphisms of the XRCC1, XRCC3, & XPD genes, and colorectal cancer risk: a case-control study in Taiwan [32].
• Genomic DNA isolated from 10 ml whole blood was used to genotype XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis [32].

References