title: Synergistic interactions between XPC and p53 mutations in double-mutant mice: neural tube abnormalities and accelerated UV radiation-induced skin cancer.
abstract: The significance of DNA repair to human health has been well documented by studies on xeroderma pigmentosum (XP) patients, who suffer a dramatically increased risk of cancer in sun-exposed areas of their skin [1,2]. This autosomal recessive disorder has been directly associated with a defect in nucleotide excision-repair (NER) [1,2]. Like human XP individuals, mice carrying homozygous mutations in XP genes manifest a predisposition to skin carcinogenesis following exposure to ultraviolet (UV) radiation [3-5]. Recent studies have suggested that, in addition to roles in apoptosis [6] and cell-cycle checkpoint control [7] in response to DNA damage, p53 protein may modulate NER [8]. Mutations in the p53 gene have been observed in 50% of all human tumors [9] and have been implicated in both the early [10] and late [11] stages of skin cancer. To examine the consequences of a combined deficiency of the XPC and the p53 proteins in mice, we generated double-mutant animals. We document a spectrum of neural tube defects in XPC p53 mutant embryos. Additionally, we show that, following exposure to UV-B radiation, XPC p53 mutant mice have more severe solar keratosis and suffer accelerated skin cancer compared with XPC mutant mice that are wild-type with respect to p53.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Cheo
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: A T
authors.initials: AT
authors.lastname: Doughty
authors.forename: E C
authors.initials: EC
authors.lastname: Friedberg
mesh_terms: D000818:Animals; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D016296:Mutagenesis; D009436:Neural Tube Defects; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C501002:Xpc protein, mouse; C086984:XPC protein, human