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¹ Laboratory for Antigen Receptor Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan
² Division of Pathology, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
³ Evolutionary Genetics, HMRO Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
⁴ Department of Developmental Genetics, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

DNA polymerase (Pol) is a family A polymerase that contains an intrinsic helicase domain. To investigate the function of Pol in mammalian cells, we have inactivated its polymerase activity in CH12 mouse B lymphoma cells by targeted deletion of the polymerase core domain that contains the catalytic aspartic acid residue. Compared to parental CH12 cells, mutant cells devoid of Pol polymerase activity exhibited a slightly reduced growth rate, accompanied by increased spontaneous cell death. In addition, mutant cells showed elevated sensitivity to mitomycin C, cisplatin, etoposide, -irradiation and ultraviolet (UV) radiation. Interestingly, mutant cells were more sensitive to the alkylating agent methyl methanesulfonate (MMS) than parental cells. This elevated MMS sensitivity relative to WT cells persisted in the presence of methoxyamine, an inhibitor of the major base excision repair (BER) pathway, suggesting that Pol is involved in tolerance of MMS through a mechanism that appears to be different from BER. These results reveal an important role for Pol in preventing spontaneous cell death and in tolerance of not only DNA interstrand cross-links and double strand breaks but also UV adducts and alkylation damage in mammalian lymphocytes.

^* Correspondence: E-mail: oh{at}rcai.riken.jp

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