Trapped in translocation: Stalling of XPD on a crosslinked DNA substrate

The superfamily 2 (SF2) helicase XPD is a central component of the general transcription factor II H (TFIIH) which is essential for transcription and nucleotide excision DNA repair (NER) 1. Within these two processes XPDs helicase function is vital for NER but not for transcription initiation, where XPD only acts as a scaffold for other factors 2. Using cryo EM, we deciphered one of the most enigmatic steps in XPD helicase action: the active separation of dsDNA and its stalling upon approaching a DNA interstrand crosslink, a highly toxic DNA damage. The structure clearly shows how dsDNA is separated and reveals a highly unusual involvement of the Arch domain in active dsDNA separation. Combined with mutagenesis and biochemical analyses, we identify distinct functional regions important for helicase activity. Surprisingly, those areas also affect core TFIIH translocase activity, revealing a yet unencountered function of XPD within the TFIIH scaffold. Importantly, our data provide a universal basis for NER bubble formation, XPD damage verification and XPG incision. ### Competing Interest Statement The authors have declared no competing interest.