Inhibition of Polo-like kinase-1 by DNA damage occurs in an ATM- or ATR-dependent fashion.
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.
van Vugt
M A
MA
Department of Molecular Biology, H-8, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Smits
V A
VA
Klompmaker
R
R
Medema
R H
RH
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004249:DNA Damage; D004268:DNA-Binding Proteins; D006801:Humans; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C576324:ATM protein, human; C576597:ATR protein, human