XRCC1

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X-ray repair complementing defective repair in Chinese hamster cells 1
Protein XRCC1 PDB 1cdz.png
PDB rendering based on 1cdz.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols XRCC1 ; RCC
External IDs OMIM194360 MGI99137 HomoloGene31368 GeneCards: XRCC1 Gene
RNA expression pattern
PBB GE XRCC1 203655 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7515 22594
Ensembl ENSG00000073050 ENSMUSG00000051768
UniProt P18887 Q60596
RefSeq (mRNA) NM_006297 NM_009532
RefSeq (protein) NP_006288 NP_033558
Location (UCSC) Chr 19:
44.05 – 44.08 Mb
Chr 7:
24.55 – 24.57 Mb
PubMed search [1] [2]

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[edit]

XRCC1_N
PDB 1xna EBI.jpg
nmr solution structure of the single-strand break repair protein xrcc1-n-terminal domain
Identifiers
Symbol XRCC1_N
Pfam PF01834
Pfam clan CL0202
InterPro IPR002706
SCOP 1xnt
SUPERFAMILY 1xnt

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]

Other function of XRCC1[edit]

In addition to its role in base excision repair, XRCC1 also has an essential role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. MMEJ is an error-prone DNA repair pathway that results in deletion mutations. XRCC1 is one of 6 proteins required for this pathway.[2]

XRCC1 over-expression in cancer[edit]

XRCC1 is over-expressed in non-small-cell lung carcinoma (NSCLC),[3] and at an even higher level in metastatic lymph nodes of NSCLC.[4]

XRCC1 under-expression in cancer[edit]

Deficiency in XRCC1, due to being heterozygous for a mutated XRCC1 gene coding for a truncated XRCC1 protein, suppresses tumor growth in mice.[5] 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[edit]

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).[6] (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.[6] (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.

Structure[edit]

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.[7]

Interactions[edit]

XRCC1 has been shown to interact with:


References[edit]

  1. ^ "Entrez Gene: XRCC1 X-ray repair complementing defective repair in Chinese hamster cells 1". 
  2. ^ Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6: e1697. doi:10.1038/cddis.2015.58. PMID 25789972. 
  3. ^ Kang CH, Jang BG, Kim DW, Chung DH, Kim YT, Jheon S et al. (2010). "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. doi:10.1016/j.lungcan.2009.07.004. PMID 19683826. 
  4. ^ Kang CH, Jang BG, Kim DW, Chung DH, Kim YT, Jheon S et al. (2009). "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. doi:10.1097/JTO.0b013e3181b9f236. PMID 19745766. 
  5. ^ Pettan-Brewer C, Morton J, Cullen S, Enns L, Kehrli KR, Sidorova J et al. (2012). "Tumor growth is suppressed in mice expressing a truncated XRCC1 protein". Am J Cancer Res 2 (2): 168–77. PMC 3304571. PMID 22432057. 
  6. ^ a b 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
  7. ^ Marintchev A, Mullen MA, Maciejewski MW, Pan B, Gryk MR, Mullen GP (Sep 1999). "Solution structure of the single-strand break repair protein XRCC1 N-terminal domain". Nature Structural Biology 6 (9): 884–93. doi:10.1038/12347. PMID 10467102. 
  8. ^ Vidal AE, Boiteux S, Hickson ID, Radicella JP (Nov 2001). "XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions". The EMBO Journal 20 (22): 6530–9. doi:10.1093/emboj/20.22.6530. PMC 125722. PMID 11707423. 
  9. ^ Date H, Igarashi S, Sano Y, Takahashi T, Takahashi T, Takano H et al. (Dec 2004). "The FHA domain of aprataxin interacts with the C-terminal region of XRCC1". Biochemical and Biophysical Research Communications 325 (4): 1279–85. doi:10.1016/j.bbrc.2004.10.162. PMID 15555565. 
  10. ^ a b Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH et al. (May 2004). "Aprataxin, a novel protein that protects against genotoxic stress". Human Molecular Genetics 13 (10): 1081–93. doi:10.1093/hmg/ddh122. PMID 15044383. 
  11. ^ Marsin S, Vidal AE, Sossou M, Ménissier-de Murcia J, Le Page F, Boiteux S et al. (Nov 2003). "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. doi:10.1074/jbc.M306160200. PMID 12933815. 
  12. ^ Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, Fraulob V et al. (Jun 2002). "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. doi:10.1074/jbc.M202390200. PMID 11948190. 
  13. ^ a b Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM (2004). "XRCC1 co-localizes and physically interacts with PCNA". Nucleic Acids Research 32 (7): 2193–201. doi:10.1093/nar/gkh556. PMC 407833. PMID 15107487. 
  14. ^ Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD et al. (Jan 2001). "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell 104 (1): 107–17. doi:10.1016/S0092-8674(01)00195-7. PMID 11163244. 
  15. ^ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931. 
  16. ^ Wang L, Bhattacharyya N, Chelsea DM, Escobar PF, Banerjee S (Nov 2004). "A novel nuclear protein, MGC5306 interacts with DNA polymerase beta and has a potential role in cellular phenotype". Cancer Research 64 (21): 7673–7. doi:10.1158/0008-5472.CAN-04-2801. PMID 15520167. 
  17. ^ 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. PMC 452490. PMID 8978692. 
  18. ^ Bhattacharyya N, Banerjee S (Jul 2001). "A novel role of XRCC1 in the functions of a DNA polymerase beta variant". Biochemistry 40 (30): 9005–13. doi:10.1021/bi0028789. PMID 11467963. 
  19. ^ 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. PMC 108937. PMID 9584196. 

Further reading[edit]

External links[edit]

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