Helicase-deficient TFIIH causes severe disease features via persistent DNA excision without damage removal
TL;DR
It is demonstrated that NER incisions can occur without XPD-mediated damage verification and that persistent futile DNA excision cycles cause severe disease features, indicating that persistent NER intermediates are more pathogenic than unrepaired DNA lesions.
Abstract
Nucleotide excision repair (NER) removes helix-distorting DNA lesions through the ten-subunit TFIIH complex, whose XPB and XPD translocase/helicase activities unwind DNA to enable damage verification and subsequent endonucleolytic DNA incisions. While most XPD mutations cause xeroderma pigmentosum, specific helicase-deficient mutations cause severe Cockayne syndrome (CS) features, including progressive neurodegeneration, for which the basis remains unclear. Here we show that loss of XPD helicase activity traps TFIIH in a futile repair cycle in which DNA is incised at the wrong position, leading to repeated DNA excision and resynthesis without removal of the lesion. Using C. elegans, we find that this futile DNA excision cycle produces severe neuronal dysfunction in vivo that depends on transcription-coupled NER activity and is rescued by preventing recruitment of helicase-deficient TFIIH. These findings demonstrate that NER incisions can occur without XPD-mediated damage verification and that persistent futile DNA excision cycles cause severe disease features, indicating that persistent NER intermediates are more pathogenic than unrepaired DNA lesions.