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Molecular and Cellular Biology, April 2008, p. 2559-2566, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01711-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Novel ATM-Dependent Pathway Regulates Protein Phosphatase 1 in Response to DNA Damage{triangledown} ,{dagger}

Xi Tang,1,2 Zhou-guang Hui,2 Xiao-li Cui,1 Renu Garg,2 Michael B. Kastan,3 and Bo Xu1*

Department of Biochemistry and Molecular Biology, Southern Research Institute, and Department of Biochemistry and Molecular Genetics and Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama 35205,1 Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112,2 Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 381053

Received 17 September 2007/ Returned for modification 17 October 2007/ Accepted 22 January 2008

Protein phosphatase 1 (PP1), a major protein phosphatase important for a variety of cellular responses, is activated in response to ionizing irradiation (IR)-induced DNA damage. Here, we report that IR induces the rapid dissociation of PP1 from its regulatory subunit inhibitor-2 (I-2) and that the process requires ataxia-telangiectasia mutated (ATM), a protein kinase central to DNA damage responses. In response to IR, ATM phosphorylates I-2 on serine 43, leading to the dissociation of the PP1-I-2 complex and the activation of PP1. Furthermore, ATM-mediated I-2 phosphorylation results in the inhibition of the Aurora-B kinase, the down-regulation of histone H3 serine 10 phosphorylation, and the activation of the G2/M checkpoint. Collectively, the results of these studies demonstrate a novel pathway that links ATM, PP1, and I-2 in the cellular response to DNA damage.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Southern Research Institute, 2000 9th Ave. South, Birmingham, AL 35205. Phone: (205) 581-2845. Fax: (205) 581-2097. E-mail: xu{at}sri.org

{triangledown} Published ahead of print on 4 February 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2008, p. 2559-2566, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01711-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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