Identification of Novel Protein Phosphatases in the ATM Signaling Pathway

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DESCRIPTION (provided by applicant): Upon DNA damage stress, the ATM kinase is rapidly phosphorylated and activated, which stimulates cell cycle arrest, cellular senescence, DNA repair, and apoptosis. When the cell is returning to its normal state following DNA repair, the ATM signaling pathway needs to be simultaneously inhibited. Very little is known about how the DNA damage response is 'deactivated' following repair. Recent evidence suggests that protein phosphatases contribute to closing the activation loop initiated by the ATM/ATR kinases to provide a homeostatic regulation. Our preliminary results showed that wildtype p53-induced phosphatase 1 (Wip1) inhibits ATM-p53 pathway by dephosphorylating several ATM targeted proteins. In particular, Wip1 stabilizes Mdm2 and MdmX by dephosphorylating their ATM phosphorylation site, resulting in decreased levels and activity of p53. If aberrantly regulated, Wip1 becomes an oncogenic phosphatase that inhibits the DNA damage response and p53 tumor suppressor pathways. We generated an expression library of human serine/threonine protein phosphatases, from which several novel phosphatases were identified as potential modulators in the ATM-p53 pathway. The hypothesis to be tested is that Wip1 and other inhibitory protein phosphatases may suppress DNA damage-induced p53 activity primarily through dephosphorylating and stabilizing Mdm2 and MdmX. PUBLIC HEALTH RELEVANCE: Protein phosphatases remove phosphate from proteins and deactivate them, which may provide a homeostatic regulation in the DNA damage response pathway. The goal of this research project is to (1) clarify the functions of protein phosphatases in the ATM (Ataxia Telangiectasia Mutated) initiated DNA damage response pathway; (2) determine how protein phosphatases regulate DNA damage-induced p53 activity.