期刊
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
卷 610, 期 1-2, 页码 14-20出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrgentox.2006.06.007
关键词
chromium; ATM; ATR; S-phase arrest
资金
- NCRR NIH HHS [P20 RR020152-020003, P20 RR020152-010003, P20 RR020152-037528, P20 RR020152] Funding Source: Medline
- NIEHS NIH HHS [R03 ES013301-03, R03 ES013301, R03 ES013301-01, R03 ES013301-02, ES013301] Funding Source: Medline
Hexavalent chromium (Cr[VI]) is an industrial waste product known to cause nasal and lung cancer in exposed workers. Intracellularly, Cr[VI] undergoes a series of enzymatic reductions resulting in the formation of reactive chromate intermediates and oxygen free radicals. These metabolites react with DNA to cause numerous types of genomic lesions, but the cellular response to these genotoxic insults is poorly understood. Recently, we demonstrated that in response to DNA damage induced by Cr[VI], an ataxia-telangiectasia mutated (ATM) and structural maintenance of chromosomal protein 1 (SMC1)-dependent S-phase checkpoint is activated. Interestingly, this checkpoint response was only ATM-dependent in cells exposed to low doses of Cr[VI], we demonstrate that the ATM and Rad3 related kinase, ATR, is required to activate the S-phase checkpoint. In response to all doses of Cr[VI], ATR is activated and phosphorylates SMC1 to facilitate the checkpoint. Further, chromatin binding ability of Rad17 is required for this process. Taken together, these results indicate that the Rad17-ATR-SMC1 pathway is essential for Cr[VI]-induced S-phase checkpoint activation. (c) 2006 Elsevier B.V. All rights reserved.
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