Emerging role of protein phosphatases changes the landscape of phospho-signaling in DNA damage response

Phosphorylation signaling networks have primarily been studied from an activation perspective, with protein phosphatases viewed as simple counter-balances that functioned passively in the wake of kinase activity. Indeed, there have been only sporadic efforts to investigate the independent role of phosphatases in DNA damage response (DDR). However, global phosphoproteomic analysis of the DDR revealed that over one-third of observed phosphorylation sites were down-regulated within minutes of DNA damage, suggesting a more robust role for phosphatases in DNA repair. Consistent with these observations, recent studies reveal that dephosphorylation of DNA repair factors during specific phases of the cell cycle may be a pre-requisite for their participation in the DDR. Here, we summarize recent literature and speculate on the emerging role of phosphatases in the DDR.