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

Rob Klompmaker,Marcel A.T.M. van Vugt,Veronique A.J. Smits,René H. Medema

doi:10.1074/jbc.m101831200

Abstract

Polo-like kinases play multiple roles in different phases of mitosis. We have recently shown that the mammalian polo-like kinase, Plk1, is inhibited in response to DNA damage and that this inhibition may lead to cell cycle arrests at multiple points in mitosis. Here we have investigated the role of the checkpoint kinases ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) in DNA damage-induced inhibition of Plk1. We show that inhibition of Plk1 kinase activity is efficiently blocked by the radio-sensitizing agent caffeine. Using ATM(-/-) cells we show that under certain circumstances, inhibition of Plk1 by DNA-damaging agents critically depends on ATM. In addition, we show that UV radiation also causes inhibition of Plk1, and we present evidence that this inhibition is mediated by ATR. Taken together, our data demonstrate that ATM and ATR can regulate Plk1 kinase activity in response to a variety of DNA-damaging agents.

Highlights

To monitor genomic integrity, cells are equipped with a variety of checkpoint mechanisms [1]
We have recently shown that the mammalian polo-like kinase, Plk1, is inhibited in response to DNA damage and that this inhibition may lead to cell cycle arrests at multiple points in mitosis
The results shown here indicate that the inhibition of Plk1 kinase activity, which is seen when the DNA damage checkpoint is activated, requires functional ATM kinase: 1) because the inhibition can be rescued by the addition of caffeine, shown to interfere with the function of ATM and 2) because we were able to show that Plk1 inhibition by the radiomimetic agents adriamycin and bleomycin was impaired in cells lacking functional ATM

Summary

Introduction

Cells are equipped with a variety of checkpoint mechanisms [1]. Our data demonstrate that ATM and ATR can regulate Plk1 kinase activity in response to a variety of DNA-damaging agents. We have investigated the role of the ATM and ATR checkpoint kinases in the inhibition of Plk1 by DNA damage.

Results

Conclusion