Polk mutant mice have a spontaneous mutator phenotype |
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| Authors: | J Nicole Kosarek Stancel Lisa D McDaniel Susana Velasco James Richardson Caixia Guo Errol C Friedberg |
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| Institution: | 1. Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53711, USA;2. Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;3. Department of Pathology and Biochemistry, The Gottstein Memorial Cancer Research Laboratory, University of Washington, Seattle, Washington 98195;4. Department of Medicinal Chemistry, Mass Spectrometry Center, University of Washington, Seattle, Washington 98195;5. Biostatistics and Center for Biomedical Statistics, University of Washington, Seattle, Washington 98195;6. Open Innovation Center for Drug Discovery, University of Tokyo, Tokyo 113-0033, Japan;12. Institute for Biomolecular Science, Faculty of Science, Gakushuin University, Tokyo 171-8588, Japan;8. Laboratory Animal Resource Center, University of Tsukuba, Tsukuba 305-8575, Japan;1. Dipartimento di Medicina e Scienze dell''Invecchiamento, Università degli Studi G. d''Annunzio Chieti Pescara, Facoltà di Medicina e Chirurgia, 66100 Chieti, Italy;2. Laboratorio di Fisiopatologia dello Stress Ossidativo, Centro di Scienze dell''Invecchiamento-Fondazione Università G. d''Annunzio, Università degli Studi G. d''Annunzio Chieti Pescara, Facoltà di Medicina e Chirurgia, 66100 Chieti, Italy;3. Dipartimento di Scienze Chirurgiche Sperimentali e Cliniche, Università degli Studi G. d''Annunzio Chieti Pescara, Facoltà di Medicina e Chirurgia, 66100 Chieti, Italy;4. Dipartimento di Scienze Sperimentali e Cliniche, Università degli Studi G. d’Annunzio Chieti Pescara, Facoltà di Medicina e Chirurgia, 66100 Chieti, Italy |
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| Abstract: | Mice defective for the Polk gene, which encodes DNA polymerase kappa, are viable and do not manifest obvious phenotypes. The present studies document a spontaneous mutator phenotype in Polk?/? mice. The initial indication of enhanced spontaneous mutations in these mice came from the serendipitous observation of a postulated founder mutation that manifested in multiple disease states among a cohort of mice comprising all three possible Polk genotypes. Polk?/? and isogenic wild-type controls carrying a reporter transgene (the λ-phage cII gene) were used for subsequent quantitative and qualitative studies on mutagenesis in various tissues. We observed significantly increased mutation frequencies in the kidney, liver, and lung of Polk?/? mice, but not in the spleen or testis. G:C base pairs dominated the mutation spectra of the kidney, liver, and lung. These results are consistent with the notion that Polκ is required for accurate translesion DNA synthesis past naturally occurring polycyclic guanine adducts, possibly generated by cholesterol and/or its metabolites. |
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