title: Characterization of defective nucleotide excision repair in XPC mutant mice.
abstract: Nucleotide excision repair (NER) is a fundamental process required for maintaining the integrity of the genome in cells exposed to environmental DNA damage. Humans defective in NER suffer from the hereditary cancer-prone disease xeroderma pigmentosum. In order to model this disease in mice a mutation in the mouse XPC gene was generated and used to replace a wild-type XPC allele in mouse embryonic stem cells by homologous recombination. These cells were used to derive XPC mutant mice. Fibroblasts from mutant embryos were more sensitive to the cytotoxic effects of ultraviolet light than wild-type and heterozygous cells. Repair synthesis of DNA following irradiation with ultraviolet light was reduced in these cells, indicating a defect in NER. Additionally, XPC mutant embryo fibroblasts were specifically defective in the removal of pyrimidine (6-4) pyrimidone photoproducts from the non-transcribed strand of the transcriptionally active p53 gene. Mice defective in the XPC gene appear to be an excellent model for studying the role of NER and its interaction with other proteins in the molecular pathogenesis of cancer in mammals following exposure to environmental carcinogens.
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas 75235, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Cheo
authors.forename: H J
authors.initials: HJ
authors.lastname: Ruven
authors.forename: L B
authors.initials: LB
authors.lastname: Meira
authors.forename: R E
authors.initials: RE
authors.lastname: Hammer
authors.forename: D K
authors.initials: DK
authors.lastname: Burns
authors.forename: N J
authors.initials: NJ
authors.lastname: Tappe
authors.forename: A A
authors.initials: AA
authors.lastname: van Zeeland
authors.forename: L H
authors.initials: LH
authors.lastname: Mullenders
authors.forename: E C
authors.initials: EC
authors.lastname: Friedberg
mesh_terms: D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D002460:Cell Line; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D016368:Frameshift Mutation; D016158:Genes, p53; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012867:Skin / Q000196:embryology; D014466:Ultraviolet Rays
chemical_list: D004268:DNA-Binding Proteins; C501002:Xpc protein, mouse; C034510:CTCGAG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific