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词条 XRCC1
释义

  1. Function

  2. Over-expression in cancer

  3. Under-expression in cancer

  4. Comparison with other DNA repair genes in cancer

  5. Stroke recovery

  6. Structure

  7. Interactions

  8. References

  9. Further reading

  10. External links

{{Infobox_gene}}

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

{{Infobox protein family
| align = left
| Symbol = XRCC1_N
| Name = XRCC1_N
| image = PDB 1xna EBI.jpg
| width =
| caption = nmr solution structure of the single-strand break repair protein xrcc1-n-terminal domain
| Pfam = PF01834
| Pfam_clan = CL0202
| InterPro = IPR002706
| SMART =
| PROSITE =
| MEROPS =
| SCOP = 1xnt
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}

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, polymerase beta and poly (ADP-ribose) polymerase to participate in the base excision repair pathway. It may play a role in DNA processing during meiogenesis and recombination in germ cells. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity.[1]

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.[2]

As reviewed by London,[2] XRCC1 protein has three globular domains connected by two linker segments of ~150 and 120 residues. The XRCC1 N-terminal domain binds to DNA polymerase beta, the C-terminal BRCT domain interacts with DNA ligase III alpha and the central domain contains a poly(ADP-ribose) binding motif. This central domain allows recruitment of XRCC1 to polymeric ADP-ribose that forms on PARP1 after PARP1 binds to single strand breaks. The first linker contains a nuclear localization sequence and also has a region that interacts with DNA repair protein REV1, and REV1 recruits translesion polymerases. The second linker interacts with polynucleotide kinase phosphatase ( PNKP) (that processes DNA broken ends during base excision repair), aprataxin (active in single-strand DNA repair and non-homologous end joining) and a third protein designated aprataxin- and PNKP-like factor.

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.[3]

Over-expression in cancer

XRCC1 is over-expressed in non-small-cell lung carcinoma (NSCLC),[4] and at an even higher level in metastatic lymph nodes of NSCLC.[5]

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.[6] 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 cancer syndromes).[7] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[7] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, XRCC1 mediated MMEJ repair is directly mutagenic, so in this case, over-expression, rather than under-expression, apparently leads to cancer. Reduction of mutagenic XRCC1 mediated MMEJ repair leads to reduced progression of cancer.

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.[8] 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 structure of the Xrcc1 N-terminal domain (Xrcc1 NTD) shows that the structural core is a beta-sandwich with beta-strands connected by loops, three helices and two short two-stranded beta-sheets at each connection side. The Xrcc1 NTD specifically binds single-strand break DNA (gapped and nicked) and a gapped DNA-beta-Pol complex.[9]

{{clear|left}}

Interactions

XRCC1 has been shown to interact with:

{{div col|colwidth=20em}}
  • APEX1,[10]
  • APTX,[11][12]
  • OGG1,[13]
  • PARP2,[14]
  • PCNA,[17]
  • PNKP,[15][16]
  • POLB,[17][18][19][20] and
  • PARP1.[12][21]
{{Div col end}}{{Clear}}

References

1. ^{{cite web | title = Entrez Gene: XRCC1 X-ray repair complementing defective repair in Chinese hamster cells 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7515| accessdate = }}
2. ^1 {{cite journal |vauthors=London RE |title=The structural basis of XRCC1-mediated DNA repair |journal=DNA Repair (Amst.) |volume=30 |issue= |pages=90–103 |year=2015 |pmid=25795425 |doi=10.1016/j.dnarep.2015.02.005 |url=}}
3. ^{{cite journal |vauthors=Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC |title=Homology and enzymatic requirements of microhomology-dependent alternative end joining |journal=Cell Death Dis |volume=6 |issue= |pages=e1697 |year=2015 |pmid=25789972 |doi=10.1038/cddis.2015.58 |url= |pmc=4385936}}
4. ^{{cite journal |vauthors=Kang CH, Jang BG, Kim DW, Chung DH, Kim YT, Jheon S, Sung SW, Kim JH |title=The prognostic significance of ERCC1, BRCA1, XRCC1, and betaIII-tubulin expression in patients with non-small cell lung cancer treated by platinum- and taxane-based neoadjuvant chemotherapy and surgical resection |journal=Lung Cancer |volume=68 |issue=3 |pages=478–83 |year=2010 |pmid=19683826 |doi=10.1016/j.lungcan.2009.07.004 |url=}}
5. ^{{cite journal |vauthors=Kang CH, Jang BG, Kim DW, Chung DH, Kim YT, Jheon S, Sung SW, Kim JH |title=Differences in the expression profiles of excision repair crosscomplementation group 1, x-ray repair crosscomplementation group 1, and betaIII-tubulin between primary non-small cell lung cancer and metastatic lymph nodes and the significance in mid-term survival |journal=J Thorac Oncol |volume=4 |issue=11 |pages=1307–12 |year=2009 |pmid=19745766 |doi=10.1097/JTO.0b013e3181b9f236 |url=}}
6. ^{{cite journal |vauthors=Pettan-Brewer C, Morton J, Cullen S, Enns L, Kehrli KR, Sidorova J, Goh J, Coil R, Ladiges WC |title=Tumor growth is suppressed in mice expressing a truncated XRCC1 protein |journal=Am J Cancer Res |volume=2 |issue=2 |pages=168–77 |year=2012 |pmid=22432057 |pmc=3304571 |doi= |url=}}
7. ^1 Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), {{ISBN|978-953-51-1114-6}}, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
8. ^{{cite journal |vauthors=Ghosh S, Canugovi C, Yoon JS, Wilson DM, Croteau DL, Mattson MP, Bohr VA |title=Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice |journal=Neurobiol. Aging |volume=36 |issue=7 |pages=2319–2330 |date=July 2015 |pmid=25971543 |pmc=5576895 |doi=10.1016/j.neurobiolaging.2015.04.004 |url=}}
9. ^{{cite journal | vauthors = Marintchev A, Mullen MA, Maciejewski MW, Pan B, Gryk MR, Mullen GP | title = Solution structure of the single-strand break repair protein XRCC1 N-terminal domain | journal = Nature Structural Biology | volume = 6 | issue = 9 | pages = 884–93 | date = Sep 1999 | pmid = 10467102 | doi = 10.1038/12347 }}
10. ^{{cite journal | vauthors = Vidal AE, Boiteux S, Hickson ID, Radicella JP | title = XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions | journal = The EMBO Journal | volume = 20 | issue = 22 | pages = 6530–9 | date = Nov 2001 | pmid = 11707423 | pmc = 125722 | doi = 10.1093/emboj/20.22.6530 }}
11. ^{{cite journal | vauthors = Date H, Igarashi S, Sano Y, Takahashi T, Takahashi T, Takano H, Tsuji S, Nishizawa M, Onodera O | title = The FHA domain of aprataxin interacts with the C-terminal region of XRCC1 | journal = Biochemical and Biophysical Research Communications | volume = 325 | issue = 4 | pages = 1279–85 | date = Dec 2004 | pmid = 15555565 | doi = 10.1016/j.bbrc.2004.10.162 }}
12. ^1 {{cite journal | vauthors = Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH, Gatti R, Date H, Onodera O, Taucher-Scholz G, Lavin MF | title = Aprataxin, a novel protein that protects against genotoxic stress | journal = Human Molecular Genetics | volume = 13 | issue = 10 | pages = 1081–93 | date = May 2004 | pmid = 15044383 | doi = 10.1093/hmg/ddh122 }}
13. ^{{cite journal | vauthors = Marsin S, Vidal AE, Sossou M, Ménissier-de Murcia J, Le Page F, Boiteux S, de Murcia G, Radicella JP | title = Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGG1 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 45 | pages = 44068–74 | date = Nov 2003 | pmid = 12933815 | doi = 10.1074/jbc.M306160200 }}
14. ^{{cite journal | vauthors = Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, Fraulob V, Ménissier-de Murcia J, de Murcia G | title = Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 25 | pages = 23028–36 | date = Jun 2002 | pmid = 11948190 | doi = 10.1074/jbc.M202390200 }}
15. ^{{cite journal | vauthors = Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW | title = XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair | journal = Cell | volume = 104 | issue = 1 | pages = 107–17 | date = Jan 2001 | pmid = 11163244 | doi = 10.1016/S0092-8674(01)00195-7 }}
16. ^{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Molecular Systems Biology | volume = 3 | issue = 1 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}
17. ^1 {{cite journal | vauthors = Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM | title = XRCC1 co-localizes and physically interacts with PCNA | journal = Nucleic Acids Research | volume = 32 | issue = 7 | pages = 2193–201 | year = 2004 | pmid = 15107487 | pmc = 407833 | doi = 10.1093/nar/gkh556 }}
18. ^{{cite journal | vauthors = Wang L, Bhattacharyya N, Chelsea DM, Escobar PF, Banerjee S | title = A novel nuclear protein, MGC5306 interacts with DNA polymerase beta and has a potential role in cellular phenotype | journal = Cancer Research | volume = 64 | issue = 21 | pages = 7673–7 | date = Nov 2004 | pmid = 15520167 | doi = 10.1158/0008-5472.CAN-04-2801 }}
19. ^{{cite journal | vauthors = Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T | title = Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein | journal = The EMBO Journal | volume = 15 | issue = 23 | pages = 6662–70 | date = Dec 1996 | pmid = 8978692 | pmc = 452490 | doi = }}
20. ^{{cite journal | vauthors = Bhattacharyya N, Banerjee S | title = A novel role of XRCC1 in the functions of a DNA polymerase beta variant | journal = Biochemistry | volume = 40 | issue = 30 | pages = 9005–13 | date = Jul 2001 | pmid = 11467963 | doi = 10.1021/bi0028789 }}
21. ^{{cite journal | vauthors = Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G | title = XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage | journal = Molecular and Cellular Biology | volume = 18 | issue = 6 | pages = 3563–71 | date = Jun 1998 | pmid = 9584196 | pmc = 108937 | doi = }}

Further reading

{{Refbegin | 35em}}
  • {{cite journal | vauthors = Hung RJ, Hall J, Brennan P, Boffetta P | title = Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review | journal = American Journal of Epidemiology | volume = 162 | issue = 10 | pages = 925–42 | date = Nov 2005 | pmid = 16221808 | doi = 10.1093/aje/kwi318 }}
  • {{cite journal | vauthors = Thompson LH, Brookman KW, Jones NJ, Allen SA, Carrano AV | title = Molecular cloning of the human XRCC1 gene, which corrects defective DNA strand break repair and sister chromatid exchange | journal = Molecular and Cellular Biology | volume = 10 | issue = 12 | pages = 6160–71 | date = Dec 1990 | pmid = 2247054 | pmc = 362891 | doi = }}
  • {{cite journal | vauthors = Thompson LH, Bachinski LL, Stallings RL, Dolf G, Weber CA, Westerveld A, Siciliano MJ | title = Complementation of repair gene mutations on the hemizygous chromosome 9 in CHO: a third repair gene on human chromosome 19 | journal = Genomics | volume = 5 | issue = 4 | pages = 670–9 | date = Nov 1989 | pmid = 2591959 | doi = 10.1016/0888-7543(89)90107-9 }}
  • {{cite journal | vauthors = Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J | title = The 1993-94 Généthon human genetic linkage map | journal = Nature Genetics | volume = 7 | issue = 2 Spec No | pages = 246–339 | date = Jun 1994 | pmid = 7545953 | doi = 10.1038/ng0694supp-246 }}
  • {{cite journal | vauthors = Wei Q, Xu X, Cheng L, Legerski RJ, Ali-Osman F | title = Simultaneous amplification of four DNA repair genes and beta-actin in human lymphocytes by multiplex reverse transcriptase-PCR | journal = Cancer Research | volume = 55 | issue = 21 | pages = 5025–9 | date = Nov 1995 | pmid = 7585546 | doi = }}
  • {{cite journal | vauthors = Lamerdin JE, Montgomery MA, Stilwagen SA, Scheidecker LK, Tebbs RS, Brookman KW, Thompson LH, Carrano AV | title = Genomic sequence comparison of the human and mouse XRCC1 DNA repair gene regions | journal = Genomics | volume = 25 | issue = 2 | pages = 547–54 | date = Jan 1995 | pmid = 7789989 | doi = 10.1016/0888-7543(95)80056-R }}
  • {{cite journal | vauthors = Caldecott KW, McKeown CK, Tucker JD, Ljungquist S, Thompson LH | title = An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III | journal = Molecular and Cellular Biology | volume = 14 | issue = 1 | pages = 68–76 | date = Jan 1994 | pmid = 8264637 | pmc = 358357 | doi = }}
  • {{cite journal | vauthors = Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A, de Jong P, Mohrenweiser H, Olsen A, Carrano A | title = Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers | journal = Genomics | volume = 15 | issue = 1 | pages = 133–45 | date = Jan 1993 | pmid = 8432525 | doi = 10.1006/geno.1993.1021 }}
  • {{cite journal | vauthors = Kubota Y, Nash RA, Klungland A, Schär P, Barnes DE, Lindahl T | title = Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein | journal = The EMBO Journal | volume = 15 | issue = 23 | pages = 6662–70 | date = Dec 1996 | pmid = 8978692 | pmc = 452490 | doi = }}
  • {{cite journal | vauthors = Nash RA, Caldecott KW, Barnes DE, Lindahl T | title = XRCC1 protein interacts with one of two distinct forms of DNA ligase III | journal = Biochemistry | volume = 36 | issue = 17 | pages = 5207–11 | date = Apr 1997 | pmid = 9136882 | doi = 10.1021/bi962281m }}
  • {{cite journal | vauthors = Shen MR, Jones IM, Mohrenweiser H | title = Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans | journal = Cancer Research | volume = 58 | issue = 4 | pages = 604–8 | date = Feb 1998 | pmid = 9485007 | doi = }}
  • {{cite journal | vauthors = Price EA, Bourne SL, Radbourne R, Lawton PA, Lamerdin J, Thompson LH, Arrand JE | title = Rare microsatellite polymorphisms in the DNA repair genes XRCC1, XRCC3 and XRCC5 associated with cancer in patients of varying radiosensitivity | journal = Somatic Cell and Molecular Genetics | volume = 23 | issue = 4 | pages = 237–47 | date = Jul 1997 | pmid = 9542526 | doi = 10.1007/BF02674415 }}
  • {{cite journal | vauthors = Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G | title = XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage | journal = Molecular and Cellular Biology | volume = 18 | issue = 6 | pages = 3563–71 | date = Jun 1998 | pmid = 9584196 | pmc = 108937 | doi = }}
  • {{cite journal | vauthors = Taylor RM, Wickstead B, Cronin S, Caldecott KW | title = Role of a BRCT domain in the interaction of DNA ligase III-alpha with the DNA repair protein XRCC1 | journal = Current Biology | volume = 8 | issue = 15 | pages = 877–80 | date = Jul 1998 | pmid = 9705932 | doi = 10.1016/S0960-9822(07)00350-8 }}
  • {{cite journal | vauthors = Zhou ZQ, Walter CA | title = Cloning and characterization of the promoter of baboon XRCC1, a gene involved in DNA strand-break repair | journal = Somatic Cell and Molecular Genetics | volume = 24 | issue = 1 | pages = 23–39 | date = Jan 1998 | pmid = 9776979 | doi = 10.1007/BF02677493 }}
  • {{cite journal | vauthors = Taylor RM, Moore DJ, Whitehouse J, Johnson P, Caldecott KW | title = A cell cycle-specific requirement for the XRCC1 BRCT II domain during mammalian DNA strand break repair | journal = Molecular and Cellular Biology | volume = 20 | issue = 2 | pages = 735–40 | date = Jan 2000 | pmid = 10611252 | pmc = 85188 | doi = 10.1128/MCB.20.2.735-740.2000 }}
  • {{cite journal | vauthors = Marintchev A, Robertson A, Dimitriadis EK, Prasad R, Wilson SH, Mullen GP | title = Domain specific interaction in the XRCC1-DNA polymerase beta complex | journal = Nucleic Acids Research | volume = 28 | issue = 10 | pages = 2049–59 | date = May 2000 | pmid = 10773072 | pmc = 105377 | doi = 10.1093/nar/28.10.2049 }}
  • {{cite journal | vauthors = Duell EJ, Wiencke JK, Cheng TJ, Varkonyi A, Zuo ZF, Ashok TD, Mark EJ, Wain JC, Christiani DC, Kelsey KT | title = Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells | journal = Carcinogenesis | volume = 21 | issue = 5 | pages = 965–71 | date = May 2000 | pmid = 10783319 | doi = 10.1093/carcin/21.5.965 }}
  • {{cite journal | vauthors = Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW | title = XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair | journal = Cell | volume = 104 | issue = 1 | pages = 107–17 | date = Jan 2001 | pmid = 11163244 | doi = 10.1016/S0092-8674(01)00195-7 }}
  • {{cite journal | vauthors = Dulic A, Bates PA, Zhang X, Martin SR, Freemont PS, Lindahl T, Barnes DE | title = BRCT domain interactions in the heterodimeric DNA repair protein XRCC1-DNA ligase III | journal = Biochemistry | volume = 40 | issue = 20 | pages = 5906–13 | date = May 2001 | pmid = 11352725 | doi = 10.1021/bi002701e }}
{{Refend}}

External links

  • {{MeshName|X-ray+repair+cross+complementing+protein+1}}
{{PDB Gallery|geneid=7515}}{{InterPro content|IPR002706}}

1 : Protein domains
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