Alternative titles; symbols
HGNC Approved Gene Symbol: XRCC1
Cytogenetic location: 19q13.31 Genomic coordinates (GRCh38): 19:43,543,311-43,575,527 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.31 | ?Spinocerebellar ataxia, autosomal recessive 26 | 617633 | Autosomal recessive | 3 |
The XRCC1 gene encodes a molecular scaffold protein that assembles multiprotein complexes involved in DNA single-strand break repair (summary by Hoch et al., 2017).
Human cells fused with Chinese hamster ovary (CHO) mutant lines, defective at different genes for excision repair of DNA following ultraviolet (UV) irradiation or defective in repair following X-irradiation, produce hybrids that retain the human gene that complements the defect in the CHO line when selected under conditions that require repair. To produce transgenic mice that carry a mutation in the Xrcc1 locus, Brookman et al. (1994) cloned the murine homolog of XRCC1 from both cosmid genomic and cDNA libraries. cDNA analysis indicated a 1,893-bp open reading frame encoding a protein of only 631 amino acids, compared with the 633-amino acid polypeptide of human XRCC1. Lamerdin et al. (1995) found that the human and mouse proteins share 86% sequence identity.
Whitehouse et al. (2001) reported that XRCC1 interacts with human polynucleotide kinase (PNK; 605610) in addition to its interactions with DNA polymerase-beta (POLB; 174760) and DNA ligase III (LIG3; 600940). Moreover, these 4 proteins are coassociated in multiprotein complexes in human cell extract, and together they repair single-strand breaks typical of those induced by reactive oxygen species and ionizing radiation. Strikingly, XRCC1 stimulates the DNA kinase and DNA phosphatase activities of PNK at damaged DNA termini, thereby accelerating the overall repair reaction. These data identified a novel pathway for mammalian single-strand break repair and demonstrated a concerted role for XRCC1 and PNK in the initial step of processing damaged DNA ends. In vitro, Sano et al. (2004) demonstrated that the long form of aprataxin (APTX; 606350), but not the short form, interacts with the C-terminal domain of XRCC1, suggesting that aprataxin may be involved in the repair complex.
Bhattacharyya and Banerjee (2001) found that XRCC1 interacts with a truncated POLB that is expressed in primary colorectal and breast tumors and inhibits the normal repair function of wildtype POLB. They determined that the interaction of the variant POLB and XRCC1 is required for the dominant inhibitory effect.
Loizou et al. (2004) showed that casein kinase II (CK2; see 115440) phosphorylates XRCC1 and thereby enables the assembly and activity of DNA single-strand break repair protein complexes in vitro and at sites of chromosome breakage. Inhibition of XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or by preventing CK2 activity using a highly specific inhibitor ablated the rapid repair of cellular DNA single-strand breaks by XRCC1. These data identified a direct role for CK2 in the repair of chromosome DNA strand breaks and in maintaining genetic integrity.
Luo et al. (2004) provided biochemical data to demonstrate that 2 preformed XRCC1 protein complexes exist in cycling HeLa cells. One complex contains known enzymes that are important for single-strand break repair, including LIG3, PNK, and POLB; the other is a new complex that contains LIG3 and aprataxin. Luo et al. (2004) reported the characterization of the new XRCC1 complex. XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on ser518, thr519, and thr523 largely determines aprataxin binding to XRCC1 through its FHA domain. 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. Thus, Luo et al. (2004) concluded that aprataxin plays a role to maintain the steady-state protein level of XRCC1. Luo et al. (2004) concluded that collectively, their data provide insights into the single-strand break repair molecular machinery in the cell and point to involvement of aprataxin in this process, thus linking single-strand break repair to the neurologic disease ataxia-oculomotor apraxia (208920).
Gao et al. (2011) reported that DNA ligase III is essential for mitochondrial DNA integrity but dispensable for nuclear DNA repair. Inactivation of ligase III in the mouse nervous system resulted in mtDNA loss leading to profound mitochondrial dysfunction, disruption of cellular homeostasis, and incapacitating ataxia. Similarly, inactivation of ligase III in cardiac muscle resulted in mitochondrial dysfunction and defective heart-pump function leading to heart failure. However, ligase III inactivation did not result in nuclear DNA repair deficiency, indicating essential DNA repair repair functions of Xrcc1 can occur in the absence of ligase III. Instead, Gao et al. (2011) found that ligase I was critical for DNA repair, but acted in a cooperative manner with ligase III. Additionally, ligase III deficiency did not recapitulate the hallmark features of neural Xrcc1 inactivation such as DNA damage-induced cerebellar interneuron loss, further underscoring functional separation of these DNA repair factors. Therefore, Gao et al. (2011) concluded that the biological role of ligase III is to maintain mtDNA integrity and not XRCC1-dependent DNA repair.
Simsek et al. (2011) demonstrated a crucial role for DNA ligase III in mitochondria but not in XRCC1-dependent repair. Simsek et al. (2011) used preemptive complementation to determine the viability requirement for Lig3in mammalian cells and its requirement in DNA repair. Various forms of Lig3 were introduced stably into mouse embryonic stem cells containing a conditional allele of Lig3 that could be deleted with Cre recombinase. With this approach, Gao et al. (2011) found that the mitochondrial, but not nuclear, Lig3 is required for the cellular viability. Although the catalytic function of Lig3 is required, the zinc finger and BRAC1 C-terminal-related domains of Lig3 are not. Remarkably, the viability requirement for Lig3 can be circumvented by targeting Lig1 to the mitochondria or expressing Chlorella virus DNA ligase, the minimal eukaryal nick-sealing enzyme, or Escherichia coli LigA, an NAD(+)-dependent ligase. Lig3-null cells were not sensitive to several DNA-damaging agents that sensitize Xrcc1-deficient cells. Simsek et al. (2011) concluded that their results established a role for Lig3 in mitochondria, but distinguished it from its interacting protein XRCC1.
Lamerdin et al. (1995) characterized the genomic structure of XRCC1 in humans and mice. The human gene has 17 exons and spans approximately 31.9 kb.
The first x-ray repair complementing gene (XRCC1) was mapped to 19qcen-19q13.3 on the basis of the loss of 19p markers, retention of proximal 19q markers, and loss of more distal 19q markers (Siciliano et al., 1987). By Southern analysis of DNAs from a hybrid panel using probes for the 3 DNA repair genes located on chromosome 19, Thompson et al. (1989) concluded that ERCC2 (126340) is distal to XRCC1 and in the same region, namely 19q13.2-q13.3, as ERCC1 (126380), but on different MluI macrorestriction fragments. Similar experiments using a hybrid clone panel containing segregating Chinese hamster chromosomes showed that the hamster homologs of the 3 repair genes are part of a highly conserved linkage group on Chinese hamster chromosome 9. The hemizygosity of hamster chromosome 9 in CHO cells can account for the high frequency at which genetically recessive mutations are recovered in these 3 genes in CHO cells. By fluorescence in situ hybridization, Trask et al. (1993) assigned the XRCC1 gene to 19q13.2.
By metaphase in situ hybridization Brookman et al. (1994) mapped the mouse Xrcc1 gene to the A3-B2 region of chromosome 7.
In a 47-year-old woman of East Indian descent with autosomal recessive spinocerebellar ataxia-26 (SCAR26; 617633), Hoch et al. (2017) identified compound heterozygous mutations in the XRCC1 gene (194360.0001 and 194360.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were demonstrated to result in significantly decreased protein levels, consistent with a loss of function. Patient cells and XRCC1-null cells showed elevated levels of protein ADP-ribosylation resulting from increased PARP1 (173870) activity. These cellular changes were similar to those observed in patients with mutations in the XRCC1 partner PNKP (605610) who have ataxia-oculomotor apraxia-4 (AOA4; 616267), which has overlapping features. The findings identified increased ADP-ribose levels as a biomarker of PARP1 hyperactivity and as a cause of cerebellar ataxia induced by unrepaired single-strand DNA breaks resulting from loss of XRCC1. Studies in mice with brain-specific Xrcc1 deletion (see ANIMAL MODEL) showed that deletion of Parp1 ablated the abnormally increased ADP-ribose levels, increased neuronal density in the cerebellum, and improved motor performance even without an effect on single-strand break repair. Hoch et al. (2017) suggested that PARP1 may be a drug target for treating cerebellar ataxias associated with unrepaired single-strand DNA break.
Hoch et al. (2017) noted that germline deletion of Xrcc1 in mice is embryonic lethal. Mice with conditional deletion of the Xrcc1 gene in the brain showed cerebellar ataxia with increased apoptosis of cerebellar granule neurons, reduced numbers of cerebellar interneurons, and decreased electrophysiologic spike activity in Purkinje cells. These changes were associated with increased levels of cerebellar ADP-ribose and hyperactivation of Parp1. Deletion of Parp1 ablated the elevated level of ADP-ribose, increased neuronal density in the cerebellum, and improved motor performance even without an effect on single-strand break repair. The data demonstrated that in the absence of Xrcc1-dependent single-strand break repair, Parp1 is hyperactivated, resulting in the loss and/or dysfunction of cerebellar neurons.
The article by Moser et al. (2007) regarding the function of XRCC1 AND LIG3 in nucleotide excision repair was retracted because an investigation at the Leiden University Medical Center concluded that 'unacceptable data manipulation by the last author Maria Fousteri led to breaches of scientific integrity, making these results unreliable.'
In a 47-year-old woman of East Indian descent with autosomal recessive spinocerebellar ataxia-26 (SCAR26; 617633), Hoch et al. (2017) identified compound heterozygous mutations in the XRCC1 gene: a c.1293G-C transversion (c.1293G-C, NM_006297) at the end of exon 11, predicted to result in a lys431-to-asn (K431N) substitution, and a c.1393C-T transition in exon 12, resulting in a gln465-to-ter (Q465X; 194360.0002) substitution. The mutations were found by exome sequencing and confirmed by Sanger sequencing. The patient's unaffected sister was heterozygous for the K431N mutation; parental DNA was not evaluated. The K431N variant was found in heterozygous state in 4 individuals of South Asian descent in the ExAC database; c.1393C-T had not previously been reported. The c.1293G-C mutation is located in a donor splice site, which could cause aberrant splicing. Both mutations were found to result in nonsense-mediated mRNA decay. Patient cells showed decreased levels of XRCC1 mRNA and protein, as well as aberrant splicing of transcripts compared to controls, consistent with a loss of function. Patient cells had about 5% residual protein levels. Functional expression studies showed that patient fibroblasts had decreased XRCC1 recruitment to the nucleus in response to DNA damage and decreased rates of single-strand break repair without an effect on double-strand break repair. Patient cells also showed an increase in sister chromatid exchange, indicative of a hyper-recombination phenotype resulting from elevated homologous recombination triggered by unrepaired single-strand breaks.
For discussion of the c.1393C-T transition (c.1393C-T, NM_006297) in exon 12 of the XRCC1 gene, resulting in a gln465-to-ter (Q465X) substitution, that was found in compound heterozygous state in a patient with autosomal recessive spinocerebellar ataxia-26 (SCAR26; 617633) by Hoch et al. (2017), see 194360.0001.
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Gao, Y., Katyal, S., Lee, Y., Zhao, J., Rehg, J. E., Russell, H. R., McKinnon, P. J. DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature 471: 240-244, 2011. [PubMed: 21390131] [Full Text: https://doi.org/10.1038/nature09773]
Hoch, N. C., Hanzlikova, H., Rulten, S. L., Tetreault, M., Komulainen, E., Ju, L., Hornyak, P., Zeng, Z., Gittens, W., Rey, S. A., Staras, K., Mancini, G. M. S., McKinnon, P. J., Wang, Z.-Q., Wagner, J. D., Care4Rare Canada Consortium, Yoon, G., Caldecott, K. W. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541: 87-91, 2017. [PubMed: 28002403] [Full Text: https://doi.org/10.1038/nature20790]
Lamerdin, J. E., Montgomery, M. A., Stilwagen, S. A., Scheidecker, L. K., Tebbs, R. S., Brookman, K. W., Thompson, L. H., Carrano, A. V. Genomic sequence comparison of the human and mouse XRCC1 DNA repair gene regions. Genomics 25: 547-554, 1995. [PubMed: 7789989] [Full Text: https://doi.org/10.1016/0888-7543(95)80056-r]
Loizou, J. I., El-Khamisy, S. F., Zlatanou, A., Moore, D. J., Chan, D. W., Qin, J., Sarno, S., Meggio, F., Pinna, L. A., Caldecott, K. W. The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks. Cell 117: 17-28, 2004. [PubMed: 15066279] [Full Text: https://doi.org/10.1016/s0092-8674(04)00206-5]
Luo, H., Chan, D. W., Yang, T., Rodriguez, M., Chen, B. P., Leng, M., Mu, J. J., Chen, D., Songyang, Z., Wang, Y., Qin, J. A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment. Molec. Cell Biol. 24: 8356-8365, 2004. [PubMed: 15367657] [Full Text: https://doi.org/10.1128/MCB.24.19.8356-8365.2004]
Moser, J., Kool, H., Giakzidis, I., Caldecott, K., Mullenders, L. H. F., Fousteri, M. I. Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase III-alpha in a cell-cycle-specific manner. Molec. Cell 27: 311-323, 2007. Note: Retraction: Molec. Cell 81: 5113 only, 2021. [PubMed: 17643379] [Full Text: https://doi.org/10.1016/j.molcel.2007.06.014]
Sano, Y., Date, H., Igarashi, S., Onodera, O., Oyake, M., Takahashi, T., Hayashi, S., Morimatsu, M., Takahashi, H., Makifuchi, T., Fukuhara, N., Tsuji, S. Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein. Ann. Neurol. 55: 241-249, 2004. [PubMed: 14755728] [Full Text: https://doi.org/10.1002/ana.10808]
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Simsek, D., Furda, A., Gao, Y., Artus, J., Brunet, E., Hadjantonakis, A.-K., Van Houten, B., Shuman, S., McKinnon, P. J., Jasin, M. Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair. Nature 471: 245-248, 2011. [PubMed: 21390132] [Full Text: https://doi.org/10.1038/nature09794]
Thompson, L. H., Bachinski, L. L., Stallings, R. L., Dolf, G., Weber, C. A., Westerveld, A., Siciliano, M. J. Complementation of repair gene mutations on the hemizygous chromosome 9 in CHO: a third repair gene on human chromosome 19. Genomics 5: 670-679, 1989. [PubMed: 2591959] [Full Text: https://doi.org/10.1016/0888-7543(89)90107-9]
Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 15: 133-145, 1993. [PubMed: 8432525] [Full Text: https://doi.org/10.1006/geno.1993.1021]
Whitehouse, C. J., Taylor, R. M., Thistlethwaite, A., Zhang, H., Karimi-Busheri, F., Lasko, D. D., Weinfeld, M., Caldecott, K. W. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104: 107-117, 2001. [PubMed: 11163244] [Full Text: https://doi.org/10.1016/s0092-8674(01)00195-7]