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129-derived Strains of Mice Are Deficient in DNA Polymerase and Have Normal Immunoglobulin Hypermutation

¹ Section on DNA Replication, Repair, and Mutagenesis, Laboratory of Genomic Integrity, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
² National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894
³ Graduate School of Frontier Biosciences, Osaka University, and CREST, Japan Science and Technology Corporation, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan
⁴ RIKEN (The Institute of Physical and Chemical Research), Wako-shi, Saitama 351-0198, Japan
⁵ Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

Address correspondence to Roger Woodgate, Laboratory of Genomic Integrity, Building 6, Room 1A13, NICHD, NIH, 9000 Rockville Pike, Bethesda, MD 20892-2725. Phone: 301-496-6175; Fax: 301-594-1135; email: woodgate{at}helix.nih.gov

Recent studies suggest that DNA polymerase (pol) and DNA polymerase (pol) are involved in somatic hypermutation of immunoglobulin variable genes. To test the role of pol in generating mutations in an animal model, we first characterized the biochemical properties of murine pol. Like its human counterpart, murine pol is extremely error-prone when catalyzing synthesis on a variety of DNA templates in vitro. Interestingly, when filling in a 1 base-pair gap, DNA synthesis and subsequent strand displacement was greatest in the presence of both pols and . Genomic sequence analysis of Poli led to the serendipitous discovery that 129-derived strains of mice have a nonsense codon mutation in exon 2 that abrogates production of pol. Analysis of hypermutation in variable genes from 129/SvJ (Poli^-/-) and C57BL/6J (Poli^+/+) mice revealed that the overall frequency and spectrum of mutation were normal in pol-deficient mice. Thus, either pol does not participate in hypermutation, or its role is nonessential and can be readily assumed by another low-fidelity polymerase.

Key Words: genomic organization • immunoglobulin variable genes • DNA polymerase • cytosine deamination • base excision repair

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