期刊
CELL CYCLE
卷 8, 期 2, 页码 299-305出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.8.2.7595
关键词
nitrosative stress; checkpoint; DNA synthesis; replication; Cdc25A; nitric oxide; Chk1; Chk2; DNA damage
类别
资金
- USPHS [CA52995]
DNA synthesis is promoted by the dephosphorylation and activation of cyclin-dependent kinase 2 (Cdk2) complexes by Cdc25A. Nitrosative stress suppresses Cdk2 dephosphorylation by Cdc25A in vitro and inhibits Cdc25A protein translation in cells, but the effects on S-phase progression remain unexamined. Herein we report that nitrosative stress catalyzed by inducible nitric oxide (center dot NO) synthase (iNOS) or the chemical nitrosant S-nitrosocysteine ethyl ester (SNCEE) rapidly inhibited DNA synthesis concomitant with Cdc25A loss. Surprisingly, this inhibition of DNA synthesis was refractory to ectopic expression of Cdc25A or a Cdc25-independent Cdk2 mutant. Nitrosative stress inhibited DNA synthesis without activating checkpoint signaling, thus distinguishing it from S-phase arrest mediated by other reactive center dot NO-derived species. The apparent lack of checkpoint activation was due to an active suppression because accumulation of pSer345-Chk1, pThr68-Chk2 and gamma H2AX was inhibited by nitrosative stress in cells exposed to DNA damage or replication inhibitors. We speculate that failure to activate the S-phase checkpoint in precancerous cells undergoing nitrosative stress may elevate the risk of transmitting damaged genomes to daughter cells upon cell cycle reentry.
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