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Carcinogenesis Advance Access published online on February 6, 2008
Carcinogenesis, doi:10.1093/carcin/bgn033
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to oxidants with increased G2/M arrest and multinucleation

Yali Xie1,2, Hanjing Yang3, Jeffrey H. Miller3, Diana M. Shih4, Geoffrey G. Hicks1,2, Jiuyong Xie1 and Robert Shiu1,2

1 Department of Physiology
2 Cell Biology Institute, University of Manitoba, 730 William Ave. Winnipeg, MB R3E 0W9, Canada
3 Department of Microbiology, Immunology, and Molecular Genetics and the Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
4 Division of Cardiology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA90095, USA

Correspondence: Y. Xie, (204) 480-1328; xiey{at}cc.umanitoba.ca or R. Shiu, (204) 789-3327; 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 (GO) 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 oxidative stress, we generated mouse embryonic fibroblast cell lines deficient in these genes. Myh and Ogg1 double knockout cells were more sensitive to oxidants (hydrogen peroxide and t-Butyl hydroperoxide), but not to cis-platinum or {gamma}-irradiations, than wild type. 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 multi-polar 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.

Key Words: Myh • Ogg1 • oxidative DNA damage repair • oxidative stress and phenotype

Received September 26, 2007; revised January 17, 2008; accepted January 26, 2008.


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