Carcinogenesis Advance Access originally published online on February 6, 2008
Carcinogenesis 2008 29(4):722-728; doi:10.1093/carcin/bgn033
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Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to oxidants with increased G2/M arrest and multinucleation
1 Department of Physiology
2 Manitoba Institute of Cell Biology, University of Manitoba, 730 William Avenue, Winnipeg, MB R3E 0W9, Canada
3 Department of Microbiology, Immunology, and Molecular Genetics and the Molecular Biology Institute
4 Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
* To whom correspondence should be addressed. Y. Xie, Tel: +1 204 480 1328; Fax: +1 204 789 3934; Email: xiey{at}cc.umanitoba.ca; or
R. Shiu, Tel: +1 204 789 3327; Fax: +1 204 789 3934; Email: rshiu{at}cc.umanitoba.ca
Oxidative stress generated from endogenous and exogenous sources causes oxidative DNA damage. The most frequent mutagenic base lesion 7,8-dihydro-8-oxoguanine and the resulting mismatched adenine are removed by OGG1 and MYH in mammals. Deficiencies in human MYH or mouse MYH and OGG1 result in tumor predisposition but the underlying molecular mechanism is not fully understood. To facilitate the study of the roles of MYH and OGG1 in the protection against oxidative stress, we generated mouse embryonic fibroblast cell lines deficient in these genes. Myh and Ogg1 double knockout cells were more sensitive than wild type to oxidants (hydrogen peroxide and t-butyl hydroperoxide), but not to cis-platinum or 
-irradiations. The low dosage oxidative stress resulted in more reduction of S phase and increase of G2/M phase in Myh–/–Ogg1–/– cells than in wild-type cells, but a similar level of cell death in both cells. The oxidants also induced more multinucleated cells in Myh–/–Ogg1–/– cells than in wild-type, accompanied by centrosome amplification and multipolar spindle formation. Thus, under oxidative stress, Myh and Ogg1 are likely required for normal cell-cycle progression and nuclear division, suggesting multiple roles of Myh and Ogg1 in the maintenance of genome stability and tumor prevention.
Abbreviations: H2O2, hydrogen peroxide; MEF, mouse embryo fibroblast; TBH, t-butyl hydroperoxide
Received September 26, 2007; revised January 17, 2008; accepted January 26, 2008.