A novel ATM-dependent pathway regulates Protein Phosphatase 1 in response to DNA damage

Department of Biochemistry and Molecular Biology, Southern Research Institute, Department of Biochemistry and Molecular Genetics, and the Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham AL, 35205; Department of Genetics, LSU Health Sciences Center, New Orleans, LA 70112; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105

^* To whom correspondence should be addressed. Email: xu{at}sri.org.

	Abstract

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 a rapid dissociation of PP1 from its regulatory subunit Inhibitor-2 (I-2) and 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 dissociation of the PP1/I-2 complex and activation of PP1. Furthermore, ATM-mediated I-2 phosphorylation results in inhibition of the Aurora-B kinase, down-regulation of Histone H3 Serine 10 phosphorylation and activation of the G2/M checkpoint. Collectively, these studies demonstrate a novel pathway that links ATM, PP1 and I-2 in the cellular response to DNA damage.