Inhibition of Polo-like kinase-1 by DNA damage occurs in an ATM- or ATR-dependent fashion

Abstract

Polo-like kinases play multiple roles in differentphases of mitosis. We have recently shown that the mammalianpolo-like kinase, Plk1, is inhibited in response toDNA damage and that this inhibition may lead to cellcycle arrests at multiple points in mitosis. Here we haveinvestigated the role of the checkpoint kinases ATM(ataxia telangiectasia mutated) and ATR (ATM- andRad3-related) in DNA damage-induced inhibition ofPlk1. We show that inhibition of Plk1 kinase activity isefficiently blocked by the radio-sensitizing agent caffeine.Using ATM/ cells we show that under certaincircumstances, inhibition of Plk1 by DNA-damagingagents critically depends on ATM. In addition, we showthat UV radiation also causes inhibition of Plk1, and wepresent evidence that this inhibition is mediated byATR. Taken together, our data demonstrate that ATMand ATR can regulate Plk1 kinase activity in response toa variety of DNA-damaging agents.