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Critical Roles for Polymerase in Cellular Tolerance to Nitric Oxide–Induced DNA Damage

¹ Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto, Japan; ² Core Research for Evolutional Science and Technology, Japan Science and Technology, Saitama, Japan; and ³ Department of Environmental and Molecular Medicine, Mie University School of Medicine, Edobashi, Tsu, Mie, Japan

Requests for reprints: Mitsuyoshi Yamazoe, Department of Radiation Genetics, Faculty of Medicine, Kyoto University, Konoe Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4410; Fax: 81-75-753-4419; E-mail: yamazoe{at}rg.med.kyoto-u.ac.jp.

Nitric oxide (NO), a signal transmitter involved in inflammation and regulation of smooth muscle and neurons, seems to cause mutagenesis, but its mechanisms have remained elusive. To gain an insight into NO-induced genotoxicity, we analyzed the effect of NO on a panel of chicken DT40 clones deficient in DNA repair pathways, including base and nucleotide excision repair, double-strand break repair, and translesion DNA synthesis (TLS). Our results show that cells deficient in Rev1 and Rev3, a subunit essential for DNA polymerase (Pol), are hypersensitive to killing by two chemical NO donors, spermine NONOate and S-nitroso-N-acetyl-penicillamine. Mitotic chromosomal analysis indicates that the hypersensitivity is caused by a significant increase in the level of induced chromosomal breaks. The data reveal the critical role of TLS polymerases in cellular tolerance to NO-induced DNA damage and suggest the contribution of these error-prone polymerases to accumulation of single base substitutions. (Cancer Res 2006; 66(2): 748-54)

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