The archetype of the ERCC6 subfamily is the human ERCC6 protein 1, also known as Cockayne Syndrome B (CSB). The S cerevisiae homologue is Rad26p 2.

Although initially regarded as repair proteins due to effects on transcription coupled nucleotide excision repair, more recent hypotheses of the function of ERCC6 has centred on their potential role in assisting transcribing RNA polymerases to either pass or dissociate from blocking DNA lesions 3. The consequent barriers to transcription elongation and sensitivity to DNA damage for non-functional mutants would explain features of Cockayne syndrome. This role is analogous to the role of the non-Snf2 family Mfd DNA translocase from E coli 4.

Interestingly, most higher animal genomes contain 3 separate genes identified as members of the ERCC6 subfamily and one Lodestar subfamily member but only a single gene in the Rad5/16 subfamily. Conversely, fungal genomes typically encode no Lodestar member, a single ERCC6 member and two or more Rad5/16 members. This may reflect divergent strategies for accomplishing transcription-coupled repair.

Although classified in the ERCC6 subfamily, the predicted sequences of the additional animal ERCC6 subfamily genes do diverge from the studied Rad26p/ERCC6.

A number of mutations in the helicase region which result in Cockayne syndrome have been identified and these map to interesting locations in the Snf2 family crystal structures 1, 5. In vitro, purified ERCC6 protein can alter nuclease sensitivity and spacing of nucleosomes in an ATP dependent manner 6. ERCC6 can also bind and negatively supercoil DNA in the presence of non-hydrolysable ATP analogues 7.