Biology:XRCC1

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Short description: Protein


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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

XRCC1_N
PDB 1xna EBI.jpg
nmr solution structure of the single-strand break repair protein xrcc1-n-terminal domain
Identifiers
SymbolXRCC1_N
PfamPF01834
Pfam clanCL0202
InterProIPR002706
SCOP21xnt / SCOPe / SUPFAM

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, i.e. during the induction of meiosis 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).[citation needed] (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.[citation needed] (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.

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.[7] 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.[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]

Interactions

XRCC1 has been shown to interact with:

References

  1. ↑ "Entrez Gene: XRCC1 X-ray repair complementing defective repair in Chinese hamster cells 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7515. 
  2. ↑ 2.0 2.1 "The structural basis of XRCC1-mediated DNA repair". DNA Repair (Amst.) 30: 90–103. 2015. doi:10.1016/j.dnarep.2015.02.005. PMID 25795425. 
  3. ↑ "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6 (3): e1697. 2015. doi:10.1038/cddis.2015.58. PMID 25789972. 
  4. ↑ "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". Lung Cancer 68 (3): 478–83. 2010. doi:10.1016/j.lungcan.2009.07.004. PMID 19683826. 
  5. ↑ "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". J Thorac Oncol 4 (11): 1307–12. 2009. doi:10.1097/JTO.0b013e3181b9f236. PMID 19745766. 
  6. ↑ "Tumor growth is suppressed in mice expressing a truncated XRCC1 protein". Am J Cancer Res 2 (2): 168–77. 2012. PMID 22432057. 
  7. ↑ "Base excision repair but not DNA double-strand break repair is impaired in aged human adipose-derived stem cells". Aging Cell 19 (2): e13062. February 2020. doi:10.1111/acel.13062. PMID 31782607. 
  8. ↑ "Partial loss of the DNA repair scaffolding protein, Xrcc1, results in increased brain damage and reduced recovery from ischemic stroke in mice". Neurobiol. Aging 36 (7): 2319–2330. July 2015. doi:10.1016/j.neurobiolaging.2015.04.004. PMID 25971543. 
  9. ↑ "Solution structure of the single-strand break repair protein XRCC1 N-terminal domain". Nature Structural Biology 6 (9): 884–93. Sep 1999. doi:10.1038/12347. PMID 10467102. 
  10. ↑ "XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions". The EMBO Journal 20 (22): 6530–9. Nov 2001. doi:10.1093/emboj/20.22.6530. PMID 11707423. 
  11. ↑ "The FHA domain of aprataxin interacts with the C-terminal region of XRCC1". Biochemical and Biophysical Research Communications 325 (4): 1279–85. Dec 2004. doi:10.1016/j.bbrc.2004.10.162. PMID 15555565. 
  12. ↑ 12.0 12.1 "Aprataxin, a novel protein that protects against genotoxic stress". Human Molecular Genetics 13 (10): 1081–93. May 2004. doi:10.1093/hmg/ddh122. PMID 15044383. 
  13. ↑ "Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGG1". The Journal of Biological Chemistry 278 (45): 44068–74. Nov 2003. doi:10.1074/jbc.M306160200. PMID 12933815. 
  14. ↑ "Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1". The Journal of Biological Chemistry 277 (25): 23028–36. Jun 2002. doi:10.1074/jbc.M202390200. PMID 11948190. 
  15. ↑ 15.0 15.1 "XRCC1 co-localizes and physically interacts with PCNA". Nucleic Acids Research 32 (7): 2193–201. 2004. doi:10.1093/nar/gkh556. PMID 15107487. 
  16. ↑ "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell 104 (1): 107–17. Jan 2001. doi:10.1016/S0092-8674(01)00195-7. PMID 11163244. 
  17. ↑ "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology 3 (1): 89. 2007. doi:10.1038/msb4100134. PMID 17353931. 
  18. ↑ "A novel nuclear protein, MGC5306 interacts with DNA polymerase beta and has a potential role in cellular phenotype". Cancer Research 64 (21): 7673–7. Nov 2004. doi:10.1158/0008-5472.CAN-04-2801. PMID 15520167. 
  19. ↑ "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. Dec 1996. doi:10.1002/j.1460-2075.1996.tb01056.x. PMID 8978692. 
  20. ↑ "A novel role of XRCC1 in the functions of a DNA polymerase beta variant". Biochemistry 40 (30): 9005–13. Jul 2001. doi:10.1021/bi0028789. PMID 11467963. 
  21. ↑ "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. Jun 1998. doi:10.1128/MCB.18.6.3563. PMID 9584196. 

Further reading

External links

This article incorporates text from the public domain Pfam and InterPro: IPR002706



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