DISRUPTION OF THE MOUSE XERODERMA-PIGMENTOSUM GROUP-D DNA-REPAIR BASAL TRANSCRIPTION GENE RESULTS IN PREIMPLANTATION LETHALITY

The xeroderma pigmentosum (XP) group D (XPD) gene encodes a DNA helica se that is a subunit of the transcription factor IIH complex, involved bath in nucleotide excision repair of UV-induced DNA damage and in ba sal transcription initiation, Point mutations in the XPD gene lead eit her to the cancer-prone repair syndrome XP, sometimes in combination w ith a second repair condition; Cockayne syndrome; or the non-cancer-pr one brittle-hair disorder trichothiodystrophy. To study the role of XP D in nucleotide excision repair and transcription and its implication in human disorders, we isolated the mouse XPD gene and generated a nul l allele via homologous recombination in embryonic stem cells by delet ing 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 offsprin g, Furthermore, we could not detect XPD-/- embryos at day 7.5 of devel opment. 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 X PD protein in mammals and in cellular viability and are consistent wit h the notion that only subtle XPD mutations are found in XP, XP/Cockay ne syndrome, and trichothiodystrophy patients.