Alternative titles; symbols
HGNC Approved Gene Symbol: XRCC3
Cytogenetic location: 14q32.33 Genomic coordinates (GRCh38): 14:103,697,617-103,715,451 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.33 | {Breast cancer, susceptibility to} | 114480 | Autosomal dominant; Somatic mutation | 3 |
| {Melanoma, cutaneous malignant, 6} | 613972 | 3 |
The mutagen-sensitive CHO line irs1SF was first isolated on the basis of hypersensitivity to ionizing radiation and was found to be chromosomally unstable as well as cross-sensitive to diverse DNA-damaging agents: ultraviolet (UV) radiation, ethyl methanesulfonate, camptothecin, and the cross-linking agents mitomycin C, cisplatin, nitrogen mustard, and melphalan. Tebbs et al. (1995) cloned a human cDNA sequence that corrected x-ray and cross-linking sensitivities, as well as spontaneous chromosomal aberrations, of irs1SF.
Liu et al. (1998) showed that XRCC3 interacts directly with RAD51 (179617) and may cooperate with RAD51 during recombinational repair.
Masson et al. (2001) found that antibody directed against RAD51C (602774) coimmunoprecipitated XRCC2 in an endogenous complex with RAD51C in HeLa cell lysates. Gel filtration of the complex suggested that a heterodimer is formed between the proteins. Using coprecipitation and multiple pull-down assays, Liu et al. (2002) confirmed interaction between these proteins. They also found that RAD51 coprecipitates with XRCC3, suggesting that RAD51 can be present in a trimeric complex of XRCC3, RAD51C, and RAD51.
Brenneman et al. (2002) found that XRCC3 mutant cells displayed radically altered homologous recombination (HR) product spectra, with increased gene conversion tract lengths, increased frequencies of discontinuous tracts, and frequent local rearrangements associated with HR. These results indicated that XRCC3 function is not limited to HR initiation, but extends to later stages in formation and resolution of HR intermediates, possibly by stabilizing heteroduplex DNA. The results further demonstrated that HR defects can promote genomic instability not only through failure to initiate HR (leading to nonhomologous repair), but also through aberrant processing of HR intermediates. The authors suggested that both mechanisms may contribute to carcinogenesis in HR-deficient cells.
Wilson et al. (2008) found that XRCC3, BRCA2 (600185), FANCD2 (227646), and FANCG (602956) formed a complex via multiple pairwise interactions following phosphorylation of FANCG. They proposed that a complex made up of at least these 4 proteins promotes homologous recombination repair of damaged DNA.
Using Western blot analysis, Sage et al. (2010) found that mitochondrial levels of RAD51, RAD51C, and XRCC3 in human cell lines increased in response to oxidative stress and weak ionizing radiation. Immunoprecipitation analysis showed that oxidative stress increased the interaction of RAD51 with mitochondrial DNA (mtDNA). Oxidative stress normally increases mtDNA copy number; however, knockdown of RAD51, RAD51C, or XRCC3 suppressed this stress response and resulted in decreased mtDNA copy number. Sage et al. (2010) concluded that proteins of the homologous recombination pathway are required to maintain the mitochondrial genome.
Tebbs et al. (1995) mapped the XRCC3 gene to human chromosome 14q32.3 by fluorescence in situ hybridization and Southern blot hybridization with genomic DNA from 2 independent hybrid clone panels.
Exposure to UV radiation is a major risk factor for the development of malignant melanoma. DNA damage caused by UV radiation is thought to play a major role in carcinogenesis. In an investigation of the association between polymorphisms in DNA repair genes and the development of malignant melanoma, Winsey et al. (2000) studied 125 individuals with malignant melanoma lesions or staging suggesting a high risk of relapse or metastatic disease. They found that the presence of a T allele at position 18067 in exon 7 of the XRCC3 gene was significantly associated with melanoma (CMM6; 613972) development (p = 0.004; odds ratio, 2.36; relative risk, 1.74).
Kuschel et al. (2002) performed genetic association studies in a population-based breast cancer case-control study analyzing polymorphisms in 7 genes involved in DNA repair. For XRCC3, there was evidence for 4 common haplotypes and 4 rarer ones that appear to have arisen by recombination. Genotype frequencies differed between cases and controls for 2 polymorphisms in XRCC3: T241M (600675.0001; P = 0.015) and IVS5 A-G at nucleotide 17893 (600675.0002; P = 0.008). Homozygous carriers of M241 were associated with an increased risk for breast cancer. Two haplotypes, AGC and GGC, were associated with nonsignificant reductions in breast cancer risk, and the rare GAT haplotype was associated with a significantly increased risk. The authors hypothesized that variability in DNA repair efficiency may alter breast cancer risk.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human XRCC3 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Winsey et al. (2000) found an association between a T allele at nucleotide 18067 in exon 7 of the XRCC3 gene and susceptibility to cutaneous malignant melanoma (613972). The 18067C-T transition was predicted to cause a thr-to-met substitution in the XRCC3 protein.
Kuschel et al. (2002) performed genetic association studies in a population-based breast cancer (see 114480) case-control study analyzing polymorphisms in 7 genes involved in DNA repair. Genotype frequencies differed between cases and controls for 2 polymorphisms in the XRCC3 gene: T241M (600675.0001; P = 0.015) and IVS5 A-G at nucleotide 17893 (p = 0.008).
Brenneman, M. A., Wagener, B. M., Miller, C. A., Allen, C., Nickoloff, J. A. XRCC3 controls the fidelity of homologous recombination: roles for XRCC3 in late stages of recombination. Molec. Cell 10: 387-395, 2002. [PubMed: 12191483] [Full Text: https://doi.org/10.1016/s1097-2765(02)00595-6]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Kuschel, B., Auranen, A., McBride, S., Novik, K. L., Antoniou, A., Lipscombe, J. M., Day, N. E., Easton, D. F., Ponder, B. A. J., Pharoah, P. D. P., Dunning, A. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum. Molec. Genet. 11: 1399-1407, 2002. [PubMed: 12023982] [Full Text: https://doi.org/10.1093/hmg/11.12.1399]
Liu, N., Lamerdin, J. E., Tebbs, R. S., Schild, D., Tucker, J. D., Shen, M. R., Brookman, K. W., Siciliano, M. J., Walter, C. A., Fan, W., Narayana, L. S., Zhou, Z.-Q., Adamson, A. W., Sorensen, K. J., Chen, D. J., Jones, N. J., Thompson, L. H. XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages. Molec. Cell 1: 783-793, 1998. [PubMed: 9660962] [Full Text: https://doi.org/10.1016/s1097-2765(00)80078-7]
Liu, N., Schild, D., Thelen, M. P., Thompson, L. H. Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells. Nucleic Acids Res. 30: 1009-1015, 2002. [PubMed: 11842113] [Full Text: https://doi.org/10.1093/nar/30.4.1009]
Masson, J.-Y., Tarsounas, M. C., Stasiak, A. Z., Stasiak, A., Shah, R., McIlwraith, M. J., Benson, F. E., West, S. C. Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev. 15: 3296-3307, 2001. [PubMed: 11751635] [Full Text: https://doi.org/10.1101/gad.947001]
Sage, J. M., Gildemeister, O. S., Knight, K. L. Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome. J. Biol. Chem. 285: 18984-18990, 2010. [PubMed: 20413593] [Full Text: https://doi.org/10.1074/jbc.M109.099846]
Tebbs, R. S., Zhao, Y., Tucker, J. D., Scheerer, J. B., Siciliano, M. J., Hwang, M., Liu, N., Legerski, R. J., Thompson, L. H. Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene. Proc. Nat. Acad. Sci. 92: 6354-6358, 1995. [PubMed: 7603995] [Full Text: https://doi.org/10.1073/pnas.92.14.6354]
Wilson, J. B., Yamamoto, K., Marriott, A. S., Hussain, S., Sung, P., Hoatlin, M. E., Mathew, C. G., Takata, M., Thompson, L. H., Kupfer, G. M., Jones, N. J. FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. Oncogene 27: 3641-3652, 2008. [PubMed: 18212739] [Full Text: https://doi.org/10.1038/sj.onc.1211034]
Winsey, S. L., Haldar, N. A., Marsh, H. P., Bunce, M., Marshall, S. E., Harris, A. L., Wojnarowska, F., Welsh, K. I. A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res. 60: 5612-5616, 2000. [PubMed: 11059748]