Abstract
Inborn defects in nucleotide excision DNA repair (NER) can paradoxically result in elevated cancer incidence (xeroderma pigmentosum [XP]) or segmental progeria without cancer predisposition (Cockayne syndrome [CS] and trichothiodystrophy [TTD]). We report generation of a knockin mouse model for the combined disorder XPCS with a G602D-encoding mutation in the Xpd helicase gene. XPCS mice are the most skin cancer-prone NER model to date, and we postulate an unusual NER dysfunction that is likely responsible for this susceptibility. XPCS mice also displayed symptoms of segmental progeria, including cachexia and progressive loss of germinal epithelium. Like CS fibroblasts, XPCS and TTD fibroblasts from human and mouse showed evidence of defective repair of oxidative DNA lesions that may underlie these segmental progeroid symptoms.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Squamous Cell / etiology
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Line, Transformed
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Cockayne Syndrome / complications
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Cockayne Syndrome / metabolism
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Cockayne Syndrome / pathology*
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DNA Repair
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Disease Models, Animal
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Disease Susceptibility
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Female
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Humans
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Male
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Mice
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Mice, Mutant Strains
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Mutation
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Papilloma / etiology
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Papilloma / metabolism
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Papilloma / pathology
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Phenotype
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Progeria / complications
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Progeria / metabolism
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Progeria / pathology*
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Skin Neoplasms / etiology
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology*
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Xeroderma Pigmentosum / complications
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Xeroderma Pigmentosum / metabolism
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Xeroderma Pigmentosum / pathology*
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Xeroderma Pigmentosum Group D Protein / genetics
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Xeroderma Pigmentosum Group D Protein / metabolism*
Substances
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Xeroderma Pigmentosum Group D Protein
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ERCC2 protein, human
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Ercc2 protein, mouse