ERCC6

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

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

Function
DNA can be damaged by ultraviolet radiation, toxins, radioactive substances, and reactive biochemical intermediates like is_associated_with::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 is_associated_with::protein, being one of the fundamental is_associated_with::enzymes in active gene repair.

Structure and Mechanism
CSB has been found to exhibit is_associated_with::ATPase properties; there are contradictory publications regarding the effect of ATP concentration on CSB's activity. The most recent evidence suggests that ADP/AMP is_associated_with::allosterically regulate CSB. 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 is_associated_with::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 is_associated_with::active site; hence, residues in these regions stabilize ATP/ADP binding via is_associated_with::hydrogen bonding. 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.

The evolutionary roots of CSB has lead some to contend that it exhibits helicase activity. 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 is_associated_with::prokaryotic precursors.

Interactions
CSB has been shown to interact with is_associated_with::P53.

CSB has been shown to act as chromatin remodeling factor for is_associated_with::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.

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

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

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

Cockayne syndrome
In humans, Cockayne syndrome (CS) is a rare autosomal recessive is_associated_with::leukodystrophy (associated with the degradation of is_associated_with::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 is_associated_with::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 is_associated_with::photosensitivity as per the heavily oxidative properties of UV light.

Implications in cancer
is_associated_with::Single-nucleotide polymorphisms in the ERCC6 gene have been correlated with significantly increased risk of certain forms of is_associated_with::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 is_associated_with::bladder cancer for experimental subjects in Taiwan; moreover, M1097V has been argued to play a key role in is_associated_with::pathogenesis. Rs1917799 polymorphism has been associated with increased risk of is_associated_with::gastric cancer for Chinese experimental subjects, and mutations at is_associated_with::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 is_associated_with::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 is_associated_with::tumor development due to malfunctioning proteins' inability to correct genes responsible for is_associated_with::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.