ERCC6

DNA excision repair protein ERCC-6 (also CS-B protein) is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23. Having 1 or more copies of a mutated ERCC6 causes Cockayne syndrome, type II.

DNA excision repair protein ERCC-6 (also CS-B protein) is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23. Having 1 or more copies of a mutated ERCC6 causes Cockayne syndrome, type II.

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.

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. 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. 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. While two copies of mutated ERCC6 result in CS, possession of a single copy of mutated ERCC6 gene is associated with similar but milder defects as CS, including retinal dystrophy, cardiac arrhythmias, and immunodeficiency. Individuals who are heterozygote carriers are therefore at increased risk of similar pleiotropic disorders as homozygote carriers afflicted with CS.

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. CSB also accumulates at sites of DNA double-strand breaks in a transcription dependent manner and influences double-strand break repair. CSB protein facilitates homologous recombinational repair of double-strand breaks and represses non-homologous end joining. 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. The CSB protein interacts with SNM1A(DCLRE1A) protein, a 5’- 3’ exonuclease, to promote the removal of DNA interstrand crosslinks.

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

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