XRCC1
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| Location (UCSC) | Chr 19: 43.54 – 43.58 Mb | Chr 7: 24.25 – 24.27 Mb | |||||||
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DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the XRCC1 gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III.
Function
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XRCC1 is involved in the efficient repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. This protein interacts with DNA ligase III,
The XRCC1 protein does not have enzymatic activity, but acts as a scaffolding protein that interacts with multiple repair enzymes. The scaffolding allows these repair enzymes to then carry out their enzymatic steps in repairing DNA. XRCC1 is involved in single-strand break repair, base excision repair and nucleotide excision repair.[6]
As reviewed by London,
XRCC1 has an essential role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. MMEJ is a highly error-prone DNA repair pathway that results in deletion mutations. XRCC1 is one of 6 proteins required for this pathway.[7]
Over-expression in cancer
XRCC1 is over-expressed in
Under-expression in cancer
Deficiency in XRCC1, due to being heterozygous for a mutated XRCC1 gene coding for a truncated XRCC1 protein, suppresses tumor growth in mice.[10] Under three experimental conditions for inducing three types of cancer (colon cancer, melanoma or breast cancer), mice heterozygous for this XRCC1 mutation had substantially lower tumor volume or number than wild type mice undergoing the same carcinogenic treatments.
Comparison with other DNA repair genes in cancer
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair proteins, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary
Aging
In aged human adipose-derived stem cells, base excision repair (BER), but not DNA double-strand break repair, is impaired. The XRCC1 protein, but not other BER factors, showed an age-associated decline.[11] Overexpression of XRCC1 reversed the age-associated decline of BER function.
Stroke recovery
Oxidative stress is increased in the brain during ischemic stroke leading to an increased burden on stress resistance mechanisms, including those for repairing oxidatively damaged DNA. Consequently any loss of a repair system that would ordinarily restore damaged DNA may impede survival and normal function of brain neurons. Ghosh et al.[12] reported that partial loss of XRCC1 function causes increased DNA damage in the brain and reduced recovery from ischemic stroke. This finding indicates that XRCC1-mediated base excision repair is important for speedy recovery from stroke.
Structure
The NMR solution
Interactions
XRCC1 has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000073050 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051768 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: XRCC1 X-ray repair complementing defective repair in Chinese hamster cells 1".
- ^ PMID 25795425.
- PMID 25789972.
- PMID 19683826.
- S2CID 30337977.
- PMID 22432057.
- PMID 31782607.
- PMID 25971543.
- S2CID 20325918.
- PMID 11707423.
- PMID 15555565.
- ^ PMID 15044383.
- PMID 12933815.
- PMID 11948190.
- ^ PMID 15107487.
- S2CID 1487128.
- PMID 17353931.
- S2CID 35569215.
- PMID 8978692.
- PMID 11467963.
- PMID 9584196.
Further reading
- Hung RJ, Hall J, Brennan P, Boffetta P (Nov 2005). "Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review". American Journal of Epidemiology. 162 (10): 925–42. PMID 16221808.
- Thompson LH, Brookman KW, Jones NJ, Allen SA, Carrano AV (Dec 1990). "Molecular cloning of the human XRCC1 gene, which corrects defective DNA strand break repair and sister chromatid exchange". Molecular and Cellular Biology. 10 (12): 6160–71. PMID 2247054.
- Thompson LH, Bachinski LL, Stallings RL, Dolf G, Weber CA, Westerveld A, Siciliano MJ (Nov 1989). "Complementation of repair gene mutations on the hemizygous chromosome 9 in CHO: a third repair gene on human chromosome 19". Genomics. 5 (4): 670–9. PMID 2591959.
- Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J (Jun 1994). "The 1993-94 Généthon human genetic linkage map". Nature Genetics. 7 (2 Spec No): 246–339. S2CID 24662426.
- Wei Q, Xu X, Cheng L, Legerski RJ, Ali-Osman F (Nov 1995). "Simultaneous amplification of four DNA repair genes and beta-actin in human lymphocytes by multiplex reverse transcriptase-PCR". Cancer Research. 55 (21): 5025–9. PMID 7585546.
- Lamerdin JE, Montgomery MA, Stilwagen SA, Scheidecker LK, Tebbs RS, Brookman KW, Thompson LH, Carrano AV (Jan 1995). "Genomic sequence comparison of the human and mouse XRCC1 DNA repair gene regions". Genomics. 25 (2): 547–54. PMID 7789989.
- Caldecott KW, McKeown CK, Tucker JD, Ljungquist S, Thompson LH (Jan 1994). "An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III". Molecular and Cellular Biology. 14 (1): 68–76. PMID 8264637.
- Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A, de Jong P, Mohrenweiser H, Olsen A, Carrano A (Jan 1993). "Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers". Genomics. 15 (1): 133–45. PMID 8432525.
- Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T (Dec 1996). "Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein". The EMBO Journal. 15 (23): 6662–70. PMID 8978692.
- Nash RA, Caldecott KW, Barnes DE, Lindahl T (Apr 1997). "XRCC1 protein interacts with one of two distinct forms of DNA ligase III". Biochemistry. 36 (17): 5207–11. PMID 9136882.
- Shen MR, Jones IM, Mohrenweiser H (Feb 1998). "Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans". Cancer Research. 58 (4): 604–8. PMID 9485007.
- Price EA, Bourne SL, Radbourne R, Lawton PA, Lamerdin J, Thompson LH, Arrand JE (Jul 1997). "Rare microsatellite polymorphisms in the DNA repair genes XRCC1, XRCC3 and XRCC5 associated with cancer in patients of varying radiosensitivity". Somatic Cell and Molecular Genetics. 23 (4): 237–47. S2CID 32956047.
- Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G (Jun 1998). "XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage". Molecular and Cellular Biology. 18 (6): 3563–71. PMID 9584196.
- Taylor RM, Wickstead B, Cronin S, Caldecott KW (Jul 1998). "Role of a BRCT domain in the interaction of DNA ligase III-alpha with the DNA repair protein XRCC1". Current Biology. 8 (15): 877–80. S2CID 17117423.
- Zhou ZQ, Walter CA (Jan 1998). "Cloning and characterization of the promoter of baboon XRCC1, a gene involved in DNA strand-break repair". Somatic Cell and Molecular Genetics. 24 (1): 23–39. S2CID 21863472.
- Taylor RM, Moore DJ, Whitehouse J, Johnson P, Caldecott KW (Jan 2000). "A cell cycle-specific requirement for the XRCC1 BRCT II domain during mammalian DNA strand break repair". Molecular and Cellular Biology. 20 (2): 735–40. PMID 10611252.
- Marintchev A, Robertson A, Dimitriadis EK, Prasad R, Wilson SH, Mullen GP (May 2000). "Domain specific interaction in the XRCC1-DNA polymerase beta complex". Nucleic Acids Research. 28 (10): 2049–59. PMID 10773072.
- Duell EJ, Wiencke JK, Cheng TJ, Varkonyi A, Zuo ZF, Ashok TD, Mark EJ, Wain JC, Christiani DC, Kelsey KT (May 2000). "Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells" (PDF). Carcinogenesis. 21 (5): 965–71. PMID 10783319.
- Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW (Jan 2001). "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell. 104 (1): 107–17. S2CID 1487128.
- Dulic A, Bates PA, Zhang X, Martin SR, Freemont PS, Lindahl T, Barnes DE (May 2001). "BRCT domain interactions in the heterodimeric DNA repair protein XRCC1-DNA ligase III". Biochemistry. 40 (20): 5906–13. PMID 11352725.
External links
- X-ray+repair+cross+complementing+protein+1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P18887 (DNA repair protein XRCC1) at the PDBe-KB.
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