LAUSR

Significance Nucleotide excision DNA repair (NER) removes a large variety of genomic lesions. NER can be initiated through two distinct pathways: global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Both pathways subsequently funnel into a common pathway that involves recruitment of the transcription factor IIH (TFIIH) complex and the central scaffold protein XPA that enables full NER complex assembly. Although downstream steps after damage recognition are thought to be identical, we identify a disease-associated mutation in XPA that severely weakens the interaction with the TFIIH complex causing TC-NER to be affected to a greater extent than GG-NER. This differential impact on GG-NER and TC-NER suggests unanticipated mechanistic differences in the transition from lesion recognition to dual incision for the two pathways of NER.