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Mutation Frequencies and Spectra in DNA Polymerase –Deficient Mice

¹ Buck Institute for Age Research, Novato, California; ² Department of Biological Technologies, Wyeth Research, Cambridge, Massachusetts; ³ Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ⁴ Harvard Medical School-Partners Healthcare Center for Genetics and Genomics and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Jan Vijg, Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945. Phone: 415-493-3636; Fax: 415-493-3640; E-mail: jvijg{at}buckinstitute.org.

Key Words: lacZ • mutations • polymerase

The low-fidelity polymerase (pol) is required for bypass of UV-induced pyrimidine dimers inserting adenine nucleotides opposite these lesions. Mutations in the pol gene are responsible for the genetic defect in xeroderma pigmentosum variant patients. To study if the lack of pol significantly elevates spontaneous mutation frequency in various organs and tissues of the mouse, we crossed pol-deficient mice with transgenic mice harboring a chromosomally integrated lacZ-plasmid reporter construct. In cultured embryonic fibroblasts from the lacZ-pol^–/– mice, 2.5 J/m² UV irradiation induced 5-fold more mutations than in cells from lacZ control mice, in which an 3-fold increase in mutation frequency was found compared with the normal level. Whereas untreated cells harbored mainly 1-bp deletions, UV induced both transitions and transversions, with the latter type more highly represented in the pol-null cells than in the controls. No difference in mutation induction between the pol-null cells and the wild-type cells was observed after treatment with N-ethyl-N-nitrosourea. Having shown the validity of the lacZ model to accurately identify pol-associated mutagenesis, we then determined the mutant frequency at the lacZ locus in liver, spleen, and small intestine of 12-month-old animals. No differences were found between pol-null, heterozygous, or littermate control mice. We conclude that the pol defect is specific for UV damage and has no effect on in vivo mutagenesis in mice. [Cancer Res 2008;68(7):2081–4]

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