title: Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients.
abstract: Mutations in the XPD gene result in xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), the phenotypes of which are often intricate. To understand the genotype/phenotype relationship, we engineered recombinant TFIIHs in which XPD subunits carry amino acid changes found in XPD patients. We demonstrate that all the XPD mutations are detrimental for XPD helicase activity, thus explaining the NER defect. We also show that TFIIH from TTD patients, but not from XP patients, exhibits a significant in vitro basal transcription defect in addition to a reduced intracellular concentration. Moreover, when XPD mutations prevent interaction with the p44 subunit of TFIIH, transactivation directed by certain nuclear receptors is inhibited, regardless of TTD versus XP phenotype, thus explaining the overlapping symptoms. The implications of these mutations are discussed using a structural model of the XPD protein. Our study provides explanations for the nature and the severity of the various clinical features.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Dubaele
authors.forename: Luca
authors.initials: L
authors.lastname: Proietti De Santis
authors.forename: Rachelle J
authors.initials: RJ
authors.lastname: Bienstock
authors.forename: Anne
authors.initials: A
authors.lastname: Keriel
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006201:Hair Diseases / Q000235:genetics*; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D007313:Insecta; D008958:Models, Molecular; D017354:Point Mutation; D011506:Proteins / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human