Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to oxidants with increased G2/M arrest and multinucleation.
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 gamma-irradiations. The low dosage oxidative stress resulted in more reduction of S phase and increase of G(2)/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.
Xie
Yali
Y
Department of Physiology, University of Manitoba, 730 William Avenue, Winnipeg, MB R3E 0W9, Canada. xiey@cc.umanitoba.ca
Yang
Hanjing
H
Miller
Jeffrey H
JH
Shih
Diana M
DM
Hicks
Geoffrey G
GG
Xie
Jiuyong
J
Shiu
Robert P
RP
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D003433:Crosses, Genetic; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency*; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D016877:Oxidants; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase