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DISRUPTION OF THE MOUSE XPD DNA REPAIR/BASAL
TRANSCRIPTION GENE RESULTS IN PREIMPLANTA TION
LETHALITY
JAN DE BOER, INGRID DONKER, JAN DE WIT, JAN H.1. HOEJJMAKERS
AND GEERT WEEDA
MGe-Dept. Cell Biology and Gcncties, Erasmus University, Rotterdam, P.G. Box
1738, 3000 DR Rotterdam, The Netherlands
The xeroderma pigmentosum (XP) group D (XPD) gene encodes a DNA helicase which
is a subunit of the TFIIH complex, involved in both nucleotide excision repair of UVinduced
DNA damage and in basal transcription initiation. Pointmutations in the XPD
gene lead either to the cancer-prone repair syndrome XP, sometimes in combination
with a second repair condition, Cockaync syndrome (CS) or the non cancer-prone
brittle-hair disorder trichothiodystrophy (TTD). To study the role of XPD in NER 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 to VI. Heterozygous cells Hnd 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- 1 . embryos at day 7.5 of development. In vitro growth experiments with
preimplantation stage embryos obtained from hcterOl,:ygolis intererosses showed a
significant higher fraction of embryos that died at the 2-cell stage, compared to wildtype
embryos. These results establish the essential function of the XPD protein in
mammals and in cellular viability and are consistent \vith the 110tion that only subtle
XPD mutations arc found in XP, XP/CS and TTD patients.
Callcer ReslYlrc/t 58:89-94 (/998)