title: Disruption of the mouse xeroderma pigmentosum group D DNA repair/basal transcription gene results in preimplantation lethality.
abstract: The xeroderma pigmentosum (XP) group D (XPD) gene encodes a DNA helicase that is a subunit of the transcription factor IIH complex, involved both in nucleotide excision repair of UV-induced DNA damage and in basal transcription initiation. Point mutations in the XPD gene lead either to the cancer-prone repair syndrome XP, sometimes in combination with a second repair condition; Cockayne syndrome; or the non-cancer-prone brittle-hair disorder trichothiodystrophy. To study the role of XPD in nucleotide excision repair and transcription and its implication in human disorders, we isolated the mouse XPD gene and generated a null allele via homologous recombination in embryonic stem cells by deleting XPD helicase domains IV-VI. Heterozygous cells and mice are normal without any obvious defect. However, when intercrossing heterozygotes, homozygous XPD mutant mice were selectively absent from the offspring. Furthermore, we could not detect XPD-/- embryos at day 7.5 of development. In vitro growth experiments with preimplantation-stage embryos obtained from heterozygous intercrosses showed a significantly higher fraction of embryos that died at the two-cell stage, compared to wild-type embryos. These results establish the essential function of the XPD protein in mammals and in cellular viability and are consistent with the notion that only subtle XPD mutations are found in XP, XP/Cockayne syndrome, and trichothiodystrophy patients.
authors.affiliation: Medical Genetics Center, Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: de Boer
authors.forename: I
authors.initials: I
authors.lastname: Donker
authors.forename: J
authors.initials: J
authors.lastname: de Wit
authors.forename: J H
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: G
authors.initials: G
authors.lastname: Weeda
mesh_terms: D000818:Animals; D002678:Chimera; D004265:DNA Helicases; D004260:DNA Repair; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins; D047108:Embryonic Development; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011247:Pregnancy; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors; D014983:Xeroderma Pigmentosum / Q000196:embryology / Q000201:enzymology / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D011506:Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; C497293:Ercc2 protein, mouse