In most cases, xeroderma pigmentosum group D (XP-D) and trichothiodystrophy (TTD) patients carry mutations in the carboxy-terminal domain of the evolutionarily conserved helicase XPD, which is one of the subunits of the transcription/repair factor TFIIH (refs 1,2). In this study, we demonstrate that XPD interacts specifically with p44, another subunit of TFIIH, and that this interaction results in the stimulation of 5'-->3' helicase activity. Mutations in the XPD C-terminal domain, as found in most patients, prevent the interaction with p44, thus explaining the decrease in XPD helicase activity and the nucleotide excision repair (NER) defect.

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Mutations in XPB, an essential subunit of the transcription/repair factor TFIIH, lead to nucleotide excision repair (NER) defects and xeroderma pigmentosum (XP). The role of XPB in NER and the molecular mechanisms resulting in XP are poorly understood. Here, we show that the p52 subunit of TFIIH interacts with XPB and stimulates its ATPase activity. A mutation found among XP-B patients (F99S) weakens this interaction and the resulting ATPase stimulation, thereby explaining the defect in the damaged DNA opening. We next found that mutations in the helicase motifs III (T469A) and VI (Q638A) that inhibit XPB helicase activity preserve the NER function of TFIIH. Our results suggest a mechanism in which the helicase activity of XPB is not used for the opening and repair of damaged DNA, which is instead only driven by its ATPase activity, in combination with the helicase activity of XPD.