XPD stalled on cross-linked DNA provides insight into damage verification

The superfamily 2 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). Within these two processes, the helicase function of XPD is vital for NER but not for transcription initiation, where...

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Bibliographic Details
Published in:	Nature structural & molecular biology Vol. 31; no. 10; pp. 1580 - 1588
Main Authors:	Kuper, Jochen, Hove, Tamsanqa, Maidl, Sarah, Neitz, Hermann, Sauer, Florian, Kempf, Maximilian, Schroeder, Till, Greiter, Elke, Höbartner, Claudia, Kisker, Caroline
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-10-2024 Nature Publishing Group
Subjects:	101/28 631/337/1427/1430 631/45/147 631/535/1258/1259 82 82/16 82/80 82/83 Adenosine triphosphate Arches Biochemistry Biological Microscopy Biomedical and Life Sciences Crosslinking Cryoelectron Microscopy Cyclin-dependent kinases Damage detection Data collection Deoxyribonucleic acid DNA DNA - chemistry DNA - metabolism DNA Damage DNA helicase DNA Repair DNA structure Genomes Humans Kinases Life Sciences Membrane Biology Models, Molecular Molecular biology Mutagenesis Nucleotides Protein Structure RNA polymerase Scaffolds Separation Transcription Factor TFIIH - chemistry Transcription Factor TFIIH - genetics Transcription Factor TFIIH - metabolism Transcription factors Translocase Verification Xeroderma Pigmentosum Group D Protein - chemistry Xeroderma Pigmentosum Group D Protein - genetics Xeroderma Pigmentosum Group D Protein - metabolism XPD protein
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Summary:	The superfamily 2 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). Within these two processes, the helicase function of XPD is vital for NER but not for transcription initiation, where XPD acts only as a scaffold for other factors. Using cryo-EM, we deciphered one of the most enigmatic steps in XPD helicase action: the active separation of double-stranded DNA (dsDNA) and its stalling upon approaching a DNA interstrand cross-link, a highly toxic form of DNA damage. The structure 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 identified 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. In summary, our data provide a universal basis for NER bubble formation, XPD damage verification and XPG incision. Here, using cryo-EM and biochemistry, the authors delineate how the XPD helicase unorthodoxly uses its Arch domain to separate double-stranded DNA upon approaching a DNA lesion, promoting our understanding of NER bubble formation and damage verification.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1545-9993 1545-9985 1545-9985
DOI:	10.1038/s41594-024-01323-5