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Cell Proliferation in Liver of Mmh/Ogg1-deficient Mice Enhances Mutation Frequency because of the Presence of 8-Hydroxyguanine in DNA

Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories, Tsukuba, Ibaraki 300-2611 [T. A., V. P. K., K. K., S. N.]; Department of Cell Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Toshima-Ku, Tokyo 170-8455 [T. A., O. M., T. N.]; Mouse Functional Genomics Research Group, RIKEN Genomic Sciences Center, Totsuka-ku, Yokohama, Kanagawa 244-0804 [O. M.]; CREST, Japan Science and Technology Corporation, Kawaguchi 332-0012 [O. M., T. N.]; and Department of Molecular Genetics, Tohoku University School of Medicine, Aoba-Ku, Sendai 980-8575 [T. N.], Japan

The Mmh/Ogg1 gene product maintains the integrity of the genome by removing the damaged base 8-hydroxyguanine (8-OH-G), one of the major DNA lesions generated by reactive oxygen species. Using Ogg1-deficient mice, we sought to establish if cells having high amounts of 8-OH-G have the ability to proliferate and whether the mutation frequency increases after proliferation in vivo. When KBrO₃, a known renal carcinogen, at a dose of 2 grams/liter was administered to Ogg1 mutant mice for 12 weeks, the amount of 8-OH-G in liver DNA from treated Ogg1^-/- mice increased 26.1 times that of treated Ogg1^+/+ mice. The accumulated 8-OH-G did not decrease 4 weeks after cessation of KBrO₃ treatment. Partial hepatectomy was performed on Ogg1^+/- and Ogg1^-/- mice after being treated with KBrO₃ for 12 weeks. The remnant liver from Ogg1^-/- mice treated with KBrO₃ regenerated to the same extent as nontreated Ogg1^+/- mice. In addition, 8-OH-G was not repaired during cell proliferation by partial hepatectomy, indicating that there is no replication coupled repair of preexisting 8-OH-G. The mutation frequency after the regeneration of liver from treated Ogg1^-/- mice showed a 3.5-fold increase compared with before regeneration. This represents a mutation frequency 6.2 times that of normal levels. The proliferation of cells having accumulated amounts of 8-OH-G caused mainly GCTA transversions. These results showed that inactivation of the Ogg1 gene leads to a higher risk of cancer because cells with accumulated 8-OH-G still retain the ability to proliferate, leading to an increase in the mutation frequency.

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