title: Abnormal XPD-induced nuclear receptor transactivation in DNA repair disorders: trichothiodystrophy and xeroderma pigmentosum.
abstract: XPD (ERCC2) is a DNA helicase involved in nucleotide excision repair and in transcription as a structural bridge tying the transcription factor IIH (TFIIH) core with the cdk-activating kinase complex, which phosphorylates nuclear receptors. Mutations in XPD are associated with several different phenotypes, including trichothiodystrophy (TTD), with sulfur-deficient brittle hair, bone defects, and developmental abnormalities without skin cancer, xeroderma pigmentosum (XP), with pigmentary abnormalities and increased skin cancer, or XP/TTD with combined features, including skin cancer. We describe the varied clinical features and mutations in nine patients examined at the National Institutes of Health who were compound heterozygotes for XPD mutations but had different clinical phenotypes: four TTD, three XP, and two combined XP/TTD. We studied TFIIH-dependent transactivation by nuclear receptor for vitamin D (VDR) and thyroid in cells from these patients. The vitamin D stimulation ratio of CYP24 and osteopontin was associated with specific pairs of mutations (reduced in 5, elevated in 1) but not correlated with distinct clinical phenotypes. Thyroid receptor stimulation ratio for KLF9 was not significantly different from normal. XPD mutations frequently were associated with abnormal VDR stimulation in compound heterozygote patients with TTD, XP, or XP/TTD.
authors.affiliation: DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhou
authors.forename: Sikandar G
authors.initials: SG
authors.lastname: Khan
authors.forename: Deborah
authors.initials: D
authors.lastname: Tamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueda
authors.forename: Jennifer
authors.initials: J
authors.lastname: Boyle
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Compe
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.forename: John J
authors.initials: JJ
authors.lastname: DiGiovanna
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kraemer
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002762:Cholecalciferol / Q000494:pharmacology; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D009154:Mutation; D053495:Osteopontin / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics; D051758:Transcription Factor TFIIH / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D054463:Trichothiodystrophy Syndromes / Q000150:complications / Q000235:genetics* / Q000473:pathology; D014284:Triiodothyronine / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase; D014815:Vitamins / Q000494:pharmacology; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D014815:Vitamins; D014284:Triiodothyronine; D053495:Osteopontin; D051758:Transcription Factor TFIIH; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human