title: Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF.
abstract: Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to DNA, XP patients are hypersensitive to sunlight and are prone to develop skin cancer. Based on the underlying genetic defect, the disease can be divided into the seven complementation groups XPA through XPG. XPF, in association with ERCC1, constitutes a structure-specific endonuclease that makes an incision 5' to the photodamage. XPF-ERCC1 has also been implicated in both removal of interstrand DNA cross-links and homology-mediated recombination and in immunoglobulin class switch recombination (CSR). To study the function of XPF in vivo, we inactivated the XPF gene in mice. XPF-deficient mice showed a severe postnatal growth defect and died approximately 3 weeks after birth. Histological examination revealed that the liver of mutant animals contained abnormal cells with enlarged nuclei. Furthermore, embryonic fibroblasts defective in XPF are hypersensitive to UV irradiation and mitomycin C treatment. No defect in CSR was detected, suggesting that the nuclease is dispensable for this recombination process. These phenotypes are identical to those exhibited by the ERCC1-deficient mice, consistent with the functional association of the two proteins. The complex phenotype suggests that XPF-ERCC1 is involved in multiple DNA repair processes.
authors.affiliation: Howard Hughes Medical Institute, and Department of Genetics, Harvard University Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tian
authors.forename: Reiko
authors.initials: R
authors.lastname: Shinkura
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Shinkura
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D005804:Genes, Lethal; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000502:physiology; D051379:Mice / Q000254:growth & development*; D016685:Mitomycin / Q000494:pharmacology; D017354:Point Mutation; D014466:Ultraviolet Rays
chemical_list: D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C095888:xeroderma pigmentosum group F protein; D016685:Mitomycin