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Molecular and Cellular Biology, September 2008, p. 5478-5493, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.02047-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Cyclin D1 Regulated by ATM or ATR Controls Cell Cycle Progression{triangledown}

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, Ohio 44195

Received 13 November 2007/ Returned for modification 22 December 2007/ Accepted 20 June 2008

Cyclin D1 is required at high levels for passage through G1 phase but must be reduced to low levels during S phase to avoid the inhibition of DNA synthesis. This suppression requires the 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 by either UV irradiation or the topoisomerase IIβ binding protein 1 activator, promoted cyclin D1 phosphorylation. Small interfering RNA 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 double-stranded DNA (dsDNA) breakage, the related checkpoint kinase ATM was also able to promote the 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.

* Corresponding author. Mailing address: Department of Molecular Genetics, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: (216) 444-0633. Fax: (216) 444-0512. E-mail: Staceyd{at}ccf.org

{triangledown} Published ahead of print on 7 July 2008.

Molecular and Cellular Biology, September 2008, p. 5478-5493, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.02047-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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