MCB Accepts, published online ahead of print on 7 July 2008

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Mol. Cell. Biol. doi:10.1128/MCB.02047-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Phosphorylation of cyclin D1 regulated by ATM or ATR controls cell cycle progression

Masahiro Hitomi, Ke Yang, Andrew W. Stacey, and Dennis W. Stacey^*

Department of Molecular Genetics, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland OH 44195

^* To whom correspondence should be addressed. Email: Staceyd{at}ccf.org.

Cyclin D1 is required at high levels for passage through G1 phase, but must be reduced to low levels during S phase to avoid inhibition of DNA synthesis. This suppression requires phosphorylation of Thr286, which is induced directly by DNA synthesis. Because the checkpoint kinase ATR is activated by normal replication as well as by DNA damage, its potential role in regulating cyclin D1 phosphorylation was tested. We found that ATR, activated either by UV irradiation or the TopBP1 activator, promoted cyclin D1 phosphorylation. siRNA against ATR inhibited UV-induced Thr286 phosphorylation, together with that seen in normally cycling cells; indicating that ATR regulates cyclin D1 phosphorylation in normal as well as stressed cells. Following dsDNA breakage, the related checkpoint kinase ATM was also able to promote phosphorylation of cyclin D1 Thr286. The relationship between these checkpoint kinases and cyclin D1 was extended when we found that normal cell cycle blockage in G1 phase observed following dsDNA damage was efficiently overcome when exogenous cyclin D1 was expressed within the cells. These results indicate that checkpoint kinases play a critical role in regulating cell cycle progression in normal and stressed cells by directing the phosphorylation of cyclin D1.

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