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Excision repair cross-complementation group 6
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM609413 MGI1100494 HomoloGene133552 GeneCards: ERCC6 Gene
Species Human Mouse
Entrez 2074 319955
Ensembl ENSG00000225830 ENSMUSG00000054051
UniProt Q03468 A3KMN2
RefSeq (mRNA) NM_000124 NM_001081221
RefSeq (protein) NP_000115 NP_001074690
Location (UCSC) Chr 10:
49.46 – 49.54 Mb
Chr 14:
32.51 – 32.58 Mb
PubMed search [1] [2]

DNA excision repair protein ERCC-6 (also CS-B protein) is a protein that in humans is encoded by the ERCC6 gene.[1][2][3] The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.[4]

Having 1 or more copies of a mutated ERCC6 causes Cockayne syndrome, type II.


DNA can be damaged by ultraviolet radiation, toxins, radioactive substances, and reactive biochemical intermediates like free radicals. The ERCC6 protein is involved in repairing the genome when specific genes undergoing transcription (dubbed active genes) are inoperative; as such, CSB serves as a transcription-coupled excision repair protein, being one of the fundamental enzymes in active gene repair.[4]

Structure and Mechanism[edit]

CSB has been found to exhibit ATPase properties; there are contradictory publications regarding the effect of ATP concentration on CSB's activity.[5] The most recent evidence suggests that ADP/AMP allosterically regulate CSB.[3] As such, it has been speculated that CSB may promote protein complex formation at repair sites subject to the ATP to ADP charge ratio.

Conservation of helicase motifs in eukaryote CSB is evident; all seven major domains of the protein are conserved among numerous RNA and DNA helicases. Detailed structural analysis of CSB has been performed; motifs I, Ia, II, and III are collectively called domain 1, while motifs IV, V, and VI comprise domain 2. These domains wrap around an interdomain cleft involved in ATP binding and hydrolysis. Motifs III and IV are in close proximity to the active site; hence, residues in these regions stabilize ATP/ADP binding via hydrogen bonding.[6] Domain 2 has been proposed to affect DNA binding after induced conformational changes stemming from ATP hydrolysis. Specific residues involved in gene binding have yet to be identified.[7]

The evolutionary roots of CSB has lead some to contend that it exhibits helicase activity.[8] Evidence for the helicase properties of CSB is highly disputed; yet, it has been found the protein participates in intracellular trafficking, a traditional role of helicases. The complex interactions between DNA repair proteins suggest that eukaryote CSB upholds some but not all of the functions of its prokaryotic precursors.[9]


CSB has been shown to interact with P53.[10][11]

CSB has been shown to act as chromatin remodeling factor for RNA Polymerase II. When RNA Polymerase II is stalled by a mistake in the genome, CSB remodels the DNA double helix so as to allow access by repair enzymes to the lesion.[12]

CSB is involved in the base excision repair (BER) pathway. This is due to demonstrated interactions with human AP endonuclease, though interactions between recombinant CSB and E. coli endonuclease IV as well as human N-terminus AP endonuclease fragments have not been observed in vitro. Specifically, CSB stimulates the AP site incision activity of AP endonuclease independent of ATP.[13]

In addition to the BER pathway, CSB is heavily integrated in the nucleotide excision repair (NER) pathway. While BER utilizes glycosylases to recognize and correct non-bulky lesions, NER is particularly versatile in repairing DNA damaged by UV radiation via the removal of oxidized bases. CSB's role in NER is best manifested by interactions with T cell receptors, in which protein collaboration is key in effective antigen binding.[14]

Neurogenesis and Neural Differentiation[edit]

ERCC6 knockout within human neural progenitor cells has been shown to decrease both neurogenesis and neural differentiation. Both mechanisms are key in brain development, explaining characteristic cognitive deficiencies of Cockayne syndrome - such as stunted development of the nervous system - that otherwise do not seem related to symptoms like photosensitivity and hearing loss.[15]

Cockayne syndrome[edit]

In humans, Cockayne syndrome (CS) is a rare autosomal recessive leukodystrophy (associated with the degradation of white matter). Mutations in ERCC6 that lead to CS deal with both the size of the protein as well as the specific amino acid residues utilized in biosynthesis. Patients exhibiting type II CS often have shortened and/or misfolded CSB that disrupt gene expression and transcription. The characteristic biological effect of malfunctioning ERCC6 is nerve cell death, resulting in premature aging and growth defects.[4]

The extent to which malfunctioning CSB hinders oxidative repair heavily influences patients' neurological functioning. The two subforms of the disorder (the latter of which corresponds to ERCC6 defects) - CS-A and CS-B - both cause problems in the oxidative repair, though CS-B patients more often exhibit nerve system problems stemming from damage to this pathway. Most type II CS patients exhibit photosensitivity as per the heavily oxidative properties of UV light.[16][17]

Implications in cancer[edit]

Single-nucleotide polymorphisms in the ERCC6 gene have been correlated with significantly increased risk of certain forms of cancer. A specific mutation at the 1097 position (M1097V) as well as polymorphisms at amino acid residue 1413 have been associated with heightened risk of bladder cancer for experimental subjects in Taiwan; moreover, M1097V has been argued to play a key role in pathogenesis.[18] Rs1917799 polymorphism has been associated with increased risk of gastric cancer for Chinese experimental subjects,[19] and mutations at codon 399 have been correlated to the onset of oral cancers among Taiwanese patients.[20] Another study found a diverse set of mutations in the ERCC6 gene among Chinese lung cancer patients versus the general population (in terms of statistical significance), but failed to identify specific polymorphisms correlated with the patients' illness.[21]

Faulty DNA repair is implicated causally in tumor development due to malfunctioning proteins' inability to correct genes responsible for apoptosis and cell growth. Yet, the vast majority of studies regarding the effects of ERCC6 knockout or mutations on cancer are based upon statistical correlations of available patient data as opposed to mechanistic analysis of in vivo cancer onset. Hence, confounding based on protein-protein, protein-substrate, and/or substrate-substrate interactions disallows conclusions positing mutations in ERCC6 cause cancer on an individual basis.


  1. ^ Troelstra C, van Gool A, de Wit J, Vermeulen W, Bootsma D, Hoeijmakers JH (Dec 1992). "ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes". Cell 71 (6): 939–53. doi:10.1016/0092-8674(92)90390-X. PMID 1339317. 
  2. ^ Muftuoglu M, de Souza-Pinto NC, Dogan A, Aamann M, Stevnsner T, Rybanska I, Kirkali G, Dizdaroglu M, Bohr VA (Apr 2009). "Cockayne syndrome group B protein stimulates repair of formamidopyrimidines by NEIL1 DNA glycosylase". The Journal of Biological Chemistry 284 (14): 9270–9. doi:10.1074/jbc.M807006200. PMC 2666579. PMID 19179336. 
  3. ^ a b "Entrez Gene: ERCC6 excision repair cross-complementing rodent repair deficiency, complementation group 6". 
  4. ^ a b c NIH. "ERCC6 Gene." Genetics Home Reference. National Institutes of Health, 16 Feb. 2015. Web. 22 Feb. 2015. <>.
  5. ^ Selby CP, Sancar A (Jan 17, 1997). "Human transcription-repair coupling factor CSB/CSB is a DNA-stimulated ATPase but is not a helicase and does not disrupt the ternary transcription complex of stalled RNA polymerase II". J Biol Chem 272 (3): 1885–90. doi:10.1074/jbc.272.3.1885. PMID 8999876. 
  6. ^ Durr H, Korner C, Muller M, Hickmann V, Hopfner KP. 2005. X-ray structures of the Sulfolobus solfataricus SWI2/SNF2 ATPase core and its complex with DNA. Cell 121:363–373.
  7. ^ Lewis R, Durr H, Hopfner KP, Michaelis J. 2008. Conformational changes of a Swi2/ Snf2 ATPase during its mechano-chemical cycle. Nucleic Acids Res 36:1881–1890.
  8. ^ Troelstra C, van Gool A, de Wit J, Vermeulen W, Bootsma D, Hoeijmakers JH (January 1993). "CSB, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes". Cell 71 (6): 939–53.
  9. ^ Boulikas, T (March–April 17, 1997). "Nuclear import of DNA repair proteins". Anticancer Research 17 (2A): 843–63. PMID 9137418.  Check date values in: |date= (help)
  10. ^ Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG (Jun 1995). "p53 modulation of TFIIH-associated nucleotide excision repair activity". Nature Genetics 10 (2): 188–95. doi:10.1038/ng0695-188. PMID 7663514. 
  11. ^ Yu A, Fan HY, Liao D, Bailey AD, Weiner AM (May 2000). "Activation of p53 or loss of the Cockayne syndrome group B repair protein causes metaphase fragility of human U1, U2, and 5S genes". Molecular Cell 5 (5): 801–10. doi:10.1016/S1097-2765(00)80320-2. PMID 10882116. 
  12. ^ Newman JC, Bailey AD, Weiner AM (Jun 2006). "Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling". Proceedings of the National Academy of Sciences of the United States of America 103 (25): 9313–8. doi:10.1073/pnas.0510909103. PMID 16772382. 
  13. ^ Wong HK, Muftuoglu M, Beck G, Imam SZ, Bohr VA, Wilson DM (June 2007). "Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates". Nucleic Acids Research 35 (12): 4103–13. doi:10.1093/nar/gkm404. PMID 17567611. 
  14. ^ Frosina G (Jul 2007). "The current evidence for defective repair of oxidatively damaged DNA in Cockayne syndrome". Free Radical Biology & Medicine 43 (2): 165–77. doi:10.1016/j.freeradbiomed.2007.04.001. PMID 17603927. 
  15. ^ Ciaffardini, F., S. Nicolai, M. Caputo, G. Canu, E. Paccosi, M. Costantino, M. Frontini, A. S. Balajee, and L. Proietti-De-Santis. "The Cockayne Syndrome B Protein Is Essential for Neuronal Differentiation and Neuritogenesis." Cell Death & Disease. Nature Publishing Group, 29 May 2014. Web. 22 Feb. 2015. <>.
  16. ^ Laugel, V., C. Dalloz, M. Durrand, and H. Dollfus. "Mutation Update for the CSB/ERCC6 and CSA/ERCC8 Genes Involved in Cockayne Syndrome." Human Mutation. Human Genome Variation Society, 5 Nov. 2009. Web. 22 Feb. 2015. <>.
  17. ^ Nardo T, Oneda R, Spivak G, Mortier L, Thomas P, Orioli D, Laugel V, Stary A, Hanawalt PC, Sarasin A, Stefanini M. 2009. A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc Natl Acad Sci USA 106:6209–6214.
  18. ^ Chang CH, Chiu CF, Wang HC, Wu HC, Tsai RY, Tsai CW, Wang RF, Wang CH, Tsou YA, Bau DT (2009). "Significant association of ERCC6 single nucleotide polymorphisms with bladder cancer susceptibility in Taiwan". Anticancer Res. 29 (12): 5121–4. PMID 20044625. 
  19. ^ Liu JW, He CY, Sun LP, Xu Q, Xing CZ, Yuan Y (2013). "The DNA repair gene ERCC6 rs1917799 polymorphism is associated with gastric cancer risk in Chinese". Asian Pac. J. Cancer Prev. 14 (10): 6103–8. doi:10.7314/apjcp.2013.14.10.6103. PMID 24289633. 
  20. ^ Chiu CF, Tsai MH, Tseng HC, Wang CL, Tsai FJ, Lin CC, Bau DT (2008). "A novel single nucleotide polymorphism in ERCC6 gene is associated with oral cancer susceptibility in Taiwanese patients". Oral Oncol. 44 (6): 582–6. doi:10.1016/j.oraloncology.2007.07.006. PMID 17933579. 
  21. ^ Ma H, Hu Z, Wang H, Jin G, Wang Y, Sun W, Chen D, Tian T, Jin L, Wei Q, Lu D, Huang W, Shen H (2009). "ERCC6/CSB gene polymorphisms and lung cancer risk". Cancer Lett. 273 (1): 172–6. doi:10.1016/j.canlet.2008.08.002. PMID 18789574. 

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