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A Novel ATM-Dependent Pathway Regulates Protein Phosphatase 1 in Response to DNA Damage ^,

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.

Published ahead of print on 4 February 2008.

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