ERCC6

DNA excision repair protein ERCC-6 (also CS-B protein) is a protein that in humans is encoded by the ERCC6 gene.[4][5][6] The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.[7]

ERCC6
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesERCC6, ARMD5, CKN2, COFS, COFS1, CSB, RAD26, UVSS1, POF11, ERCC excision repair 6, chromatin remodeling factor, excision repair cross-complementing group 6
External IDsOMIM: 609413 MGI: 1100494 HomoloGene: 133552 GeneCards: ERCC6
Orthologs
SpeciesHumanMouse
Entrez

2074

319955

Ensembl

ENSG00000225830

ENSMUSG00000054051

UniProt

P0DP91
Q8N328

F8VPZ5

RefSeq (mRNA)

n/a

NM_001081221

RefSeq (protein)

NP_000115
NP_001263987
NP_001263988
NP_001333369
NP_736609

NP_001074690

Location (UCSC)n/aChr 14: 32.51 – 32.58 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

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

Function

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, ERCC6 serves as a transcription-coupled excision repair protein, being one of the fundamental enzymes in active gene repair.[7]

Structure and Mechanism

CSB has been found to exhibit ATPase properties; there are contradictory publications regarding the effect of ATP concentration on CSB's activity.[8] The most recent evidence suggests that ADP/AMP allosterically regulate CSB.[6] 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.[9] 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.[10]

The evolutionary roots of CSB has led some to contend that it exhibits helicase activity.[11] 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.[12]

Interactions

CSB has been shown to interact with P53.[13][14]

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.[15]

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.[16]

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.[17]

Neurogenesis and Neural Differentiation

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.[18]

Cockayne syndrome

In humans, Cockayne syndrome (CS) is a rare autosomal recessive leukodystrophy (associated with the degradation of white matter). CS arises from germ line mutations in either of two genes, CSA(ERCC8) or CSB(ERCC6). About two thirds of CS patients have a mutation in the CSB(ERCC6) gene.[19] 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.[7]

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.[20][21]

DNA repair

CSB and CSA proteins are considered to function in transcription coupled nucleotide excision repair (TC-NER). CSB and CSA deficient cells are unable to preferentially repair UV-induced cyclobutane pyrimidine dimers in actively transcribed genes, consistent with a failed TC-NER response.[22] CSB also accumulates at sites of DNA double-strand breaks in a transcription dependent manner and influences double-strand break repair.[23] CSB protein facilitates homologous recombinational repair of double-strand breaks and represses non-homologous end joining.[23]

In a damaged cell, the CSB protein localizes to sites of DNA damage. CSB recruitment to damaged sites is influenced by the type of DNA damage and is, most rapid and robust as follows: interstrand crosslinks > double-strand breaks > monoadducts > oxidative damages.[19] The CSB protein interacts with SNM1A(DCLRE1A) protein, a 5’- 3’ exonuclease, to promote the removal of DNA interstrand crosslinks.[24]

Implications in cancer

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.[25] Rs1917799 polymorphism has been associated with increased risk of gastric cancer for Chinese experimental subjects,[26] and mutations at codon 399 have been correlated to the onset of oral cancers among Taiwanese patients.[27] 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.[28]

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.

References
  1. GRCm38: Ensembl release 89: ENSMUSG00000054051 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. 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. hdl:1765/3041. PMID 1339317. S2CID 30671008.
  5. 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.
  6. "Entrez Gene: ERCC6 excision repair cross-complementing rodent repair deficiency, complementation group 6".
  7. NIH. "ERCC6 Gene." Genetics Home Reference. National Institutes of Health, 16 Feb. 2015. Web. 22 Feb. 2015. <http://ghr.nlm.nih.gov/gene/ERCC6>.
  8. 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.
  9. 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 (3): 363–373. doi:10.1016/j.cell.2005.03.026. PMID 15882619.
  10. 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 (6): 1881–1890. doi:10.1093/nar/gkn040. PMC 2346605. PMID 18267970.
  11. Troelstra C, van Gool A, de Wit J, Vermeulen W, Bootsma D, Hoeijmakers JH (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. doi:10.1016/0092-8674(92)90390-x. hdl:1765/3041. PMID 1339317. S2CID 30671008.
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  14. 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.
  15. 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. PMC 1480455. PMID 16772382.
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  19. Iyama T, Wilson DM (2016). "Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome". J. Mol. Biol. 428 (1): 62–78. doi:10.1016/j.jmb.2015.11.020. PMC 4738086. PMID 26616585.
  20. 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. <http://onlinelibrary.wiley.com/doi/10.1002/humu.21154/epdf>.
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  24. Iyama T, Lee SY, Berquist BR, Gileadi O, Bohr VA, Seidman MM, McHugh PJ, Wilson DM (2015). "CSB interacts with SNM1A and promotes DNA interstrand crosslink processing". Nucleic Acids Res. 43 (1): 247–58. doi:10.1093/nar/gku1279. PMC 4288174. PMID 25505141.
  25. 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.
  26. 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.
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Further reading
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