Helicase-deficient TFIIH causes severe disease features via persistent DNA excision without damage removal

Nucleotide excision repair (NER) is a process that removes helix-distorting DNA lesions, involving the TFIIH complex composed of ten subunits. XPB and XPD translocase/helicase activities within TFIIH unwind DNA to enable damage verification and endonucleolytic DNA incisions. While most XPD mutations result in xeroderma pigmentosum, specific helicase-deficient mutations lead to severe Cockayne syndrome (CS) features, such as progressive neurodegeneration, with unclear underlying causes.

This study demonstrates that loss of XPD helicase activity traps TFIIH in a repetitive repair cycle, where DNA is incised at the wrong position, resulting in repeated DNA excision and resynthesis without removal of the lesion. Using C. elegans as a model organism, the research reveals that this futile DNA excision cycle induces severe neuronal dysfunction in vivo, which depends on transcription-coupled NER activity.

Importantly, this detrimental effect can be mitigated by preventing the recruitment of helicase-deficient TFIIH. The findings suggest that NER incisions can occur without XPD-mediated damage verification, and persistent futile DNA excision cycles can cause severe disease features, implying that persistent NER intermediates are more pathogenic than unrepaired DNA lesions.