Ascorbic acid-dehydroascorbate induces cell cycle arrest at G2/M DNA damage checkpoint during oxidative stress.
Reactive oxygen species induce cellular damage and have been implicated as mediators for cellular signaling pathways. However, a linkage between the cellular redox status and cell cycle progression has not been demonstrated. We previously demonstrated, using the Chinese hamster ovary cell line AS52, that the cytotoxic and mutagenic effects of oxidative stress is prevented by ascorbic acid (AA), but only when cells are treated with AA prior to treatment with the stressor. To elucidate the mechanism(s) responsible for this effect, we determined the effect of AA on cell cycle progression during oxidative stress. Flow cytometric analyses demonstrated that treatment of AS52 cells with AA (50 microM), prior to treatment with a radical generating system (RGS), enhanced cell cycle arrest at the G2/M DNA damage checkpoint when compared to cells treated with RGS. AA had no effect on cell cycle progression in the absence of oxidative stress. Furthermore, under conditions that prevent the reduction of dehydroascorbate (DHA), the oxidized form of AA, cell cycle arrest was also induced at the G2/M DNA damage checkpoint. These observations demonstrate that during periods of oxidative stress, AA functions as an antioxidant and DHA enhances transient arrest at the G2/M checkpoint by delaying the activation of cyclin B-cdc2. These results suggest the presence of a unique redox mechanism for the regulation of cell cycle progression and also demonstrate a novel mechanism by which AA protects cells from damage due to oxidative stress.
Bijur
G N
GN
Department of Medical Microbiology, The Ohio State University, Columbus 43210, USA.
Briggs
B
B
Hitchcock
C L
CL
Williams
M V
MV
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D006224:Cricetinae; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004249:DNA Damage; D003683:Dehydroascorbic Acid / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D018384:Oxidative Stress
D000975:Antioxidants; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019926:Cyclin B; D019328:Buthionine Sulfoximine; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid