title: In TFIIH, XPD helicase is exclusively devoted to DNA repair.
abstract: The eukaryotic XPD helicase is an essential subunit of TFIIH involved in both transcription and nucleotide excision repair (NER). Mutations in human XPD are associated with several inherited diseases such as xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. We performed a comparative analysis of XPD from Homo sapiens and Chaetomium thermophilum (a closely related thermostable fungal orthologue) to decipher the different molecular prerequisites necessary for either transcription or DNA repair. In vitro and in vivo assays demonstrate that mutations in the 4Fe4S cluster domain of XPD abrogate the NER function of TFIIH and do not affect its transcriptional activity. We show that the p44-dependent activation of XPD is promoted by the stimulation of its ATPase activity. Furthermore, we clearly demonstrate that XPD requires DNA binding, ATPase, and helicase activity to function in NER. In contrast, these enzymatic properties are dispensable for transcription initiation. XPD helicase is thus exclusively devoted to NER and merely acts as a structural scaffold to maintain TFIIH integrity during transcription.
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Kuper
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch Cedex, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Braun
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Elias
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Michels
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Sauer
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Schmitt
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch Cedex, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Poterszman
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch Cedex, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D002597:Chaetomium / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C478359:WDR77 protein, human; D051758:Transcription Factor TFIIH; D004247:DNA; D008156:Luciferases; D000251:Adenosine Triphosphatases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human