A novel ATM-dependent pathway regulates PP1 activation and the G2/M checkpoint in response to DNA damage

4205 The Ataxia-Telangiectasia Mutated kinase, ATM, plays a crucial role in the cellular response to DNA damage. Loss of ATM functions in humans results in Ataxia-Telangiectasia (A-T), an autosomal recessive disease manifested by progressive neuro-degeneration, immunodeficiency, cancer predisposition and hyper-radiosensitivity. Upon DNA damage, ATM binds strongly to damaged sites and activated ATM in turn phosphorylates a list of substrates in pathways that together ensure cellular survival and recovery. We previously reported that ATM was required for down-regulation of Histone H3 phosphorylation and the G2/M checkpoint in response to ionizing radiation (IR). However, the detailed mechanism of the processes remains unknown. It was known that Protein Phosphatase 1 (PP1), the major phosphatase responsible for Histone H3 dephosphorylation, was activated in an ATM-dependent manner after IR. In this study, we report that ATM is required for the IR-induced rapid dissociation of PP1 from its regulatory subunit Inhibitor-2 (I-2). We also find that ATM phosphorylates I-2 at Serine 43 in response to IR. ATM phosphorylation of I-2 leads to dissociation of the PP1/I-2 complex and activation of PP1. Furthermore, ATM-mediated I-2 phosphorylation results in activation of the G2/M checkpoint. These studies have demonstrated a novel pathway that links ATM, PP1 and I-2 in cellular responses to DNA damage.