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The Combined Effects of Xeroderma Pigmentosum C Deficiency and Mutagens on Mutation Rates in the Mouse Germ Line

¹ Commissariat à l'Energie Atomique, Laboratoire de Génétique de la Radiosensibilité, Institut de Radiobiologie Cellulaire et Moléculaire, Direction des Sciences du Vivant, Fontenay aux Roses, France; ² Department of Genetics, University of Leicester, Leicester, United Kingdom; and ³ Laboratory of Molecular Pathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Yuri Dubrova, Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom. Phone: 44-116-252-5654; Fax: 44-116-252-3378; E-mail: yed2{at}le.ac.uk.

Spontaneous and induced mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germ line of xeroderma pigmentosum group C (Xpc) knockout mice defective in global genome nucleotide excision repair. Spontaneous and radiation-induced mutation rates in homozygous Xpc^–/– males were significantly higher than those in isogenic wild-type (Xpc^+/+) and heterozygous (Xpc^+/–) mice. In contrast, exposure to the monofunctional alkylating agent ethylnitrosourea resulted in similar increases in ESTR mutation rates across all genotypes. ESTR mutation spectra in the germ line of Xpc^–/–, Xpc^+/– and Xpc^+/+ did not differ. Considering these data and the results of other publications, we propose that the Xpc-deficient mice possess a mutator phenotype in their germ line and somatic tissues that may significantly enhance carcinogenesis across multiple tissues. [Cancer Res 2007;67(10):4695–9]

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