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Disruption of the Mouse Xeroderma Pigmentosum Group D DNA Repair/Basal Transcription Gene Results in Preimplantation Lethality¹

Medical Genetics Center, Department of Cell Biology and Genetics, Erasmus University, 3000 DR Rotterdam, the Netherlands

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.

¹ This work was supported by the Dutch Cancer Society (Projects EUR 90-20 and 94-763) and by Research Grant RG373 from the Human Frontier Research Program. The research of G. W. has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences.

² To whom requests for reprints should be addressed, at MGC-Dept Cell Biology and Genetics, Erasmus University, P. O. Box 1738, 3000 DR Rotterdam, the Netherlands. Fax: 10-4360225.

Received 4/28/97. Accepted 10/23/97.

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