) The Werner syndrome (WS) is an autosomal recessive disorder caused by mutations at a locus (WRN) coding for a member of the RecQ family of helicases. Patients suffer from a wide variety of benign and malignant neoplasms, with a relative high load of mesenchymal tumors. WS somatic cells exhibit mutator phenotypes and elongated S phases. The applicants are generating two mouse models of WS via targeted mutagenesis, an exon 2 knockout and an exon 26 deletion, the latter emulating the commonest variety of mutation in the Japanese population. In the proposal, in addition to the characterization of genomic instability and the determination of the prevalence and spectra of various neoplasms in homozygous deficient and wild-type mice (all on a C57BL/6 background), they will carry out comparable experiments with heterozygotic carriers, which are of special public health interest, given their relative high prevalence. Treatments with genotoxic agents, 4-nitroquinoline-1 oxide (4NQO), camptothecin, and benzo[a]pyrene, will be used as models of gene-environmental interactions with these three genotypes. In future experiments, homozygotes and heterozygotes will be crossed with other transgenic mouse lines relevant to the modulation of WRN gene action.
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