The DNA helicase activity of the xeroderma pigmentosum D protein, a crucial subunit of TFIID, is only needed for its role in DNA repair, not for transcription.
The xeroderma pigmentosum group D (XPD) helicase is a subunit of transcription/DNA repair factor, transcription factor II H (TFIIH) that catalyzes the unwinding of a damaged DNA duplex during nucleotide excision repair. Apart from two canonical helicase domains, XPD is composed of a 4Fe-S cluster domain involved in DNA damage recognition and a module of uncharacterized function termed the "ARCH domain." By investigating the consequences of a mutation found in a patient with trichothiodystrophy, we show that the ARCH domain is critical for the recruitment of the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex. Indeed, this mutation not only affects the interaction with the MAT1 CAK subunit, thereby decreasing the in vitro basal transcription activity of TFIIH itself and impeding the efficient recruitment of the transcription machinery on the promoter of an activated gene, but also impairs the DNA unwinding activity of XPD and the nucleotide excision repair activity of TFIIH. We further demonstrate the role of CAK in downregulating the XPD helicase activity within TFIIH. Taken together, our results identify the ARCH domain of XPD as a platform for the recruitment of CAK and as a potential molecular switch that might control TFIIH composition and play a key role in the conversion of TFIIH from a factor active in transcription to a factor involved in DNA repair.rare disease | regulation of gene expression T he xeroderma pigmentosum group D (XPD) gene encodes a 5′-3′ helicase (XPD) that harbors mutations in patients suffering from three rare autosomal recessive diseases, xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne syndrome (CS) (1, 2). XP is characterized by a deficit of the nucleotide excision repair (NER) pathway, leading to sun sensitivity and susceptibility to skin cancer. TTD is characterized by sulfur-deficient brittle hair and a variety of neuroectodermal symptoms (3). XPD is the founding member of a family of DNA helicases conserved in archaea and eukaryotes. All family members share a four-domain organization including a conserved (Fe-S) cluster-binding domain that is essential for the helicase activity and a module of uncharacterized function named the ARCH domain by its arch-shape structure (4-7). Although archeal XPD homologs are monomers and have no known stable interactors, eukaryotic XPD homologs are part of the general transcription/DNA repair factor transcription factor II H (TFIIH), a multisubunit complex made up of 10 subunits (reviewed in ref. 8). Low-resolution models for TFIIH have been obtained for the complex in yeast (9, 10) and for the human complex (11), showing an overall conservation of shape. Human TFIIH can be resolved into two functional and structural entities bridged by XPD: the core-TFIIH consists of XPB, p62, p52, p44, p34, and p8, whereas the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex contains CDK7, cyclin H, and ménage a trois 1 (MAT1). XPD interacts with the p44 core-TFIIH subunit and with MAT1, a subunit of CAK involve...
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