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J. Biol. Chem., Vol. 280, Issue 52, 42994-42999, December 30, 2005

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The Role of Polo-like Kinase 1 in the Inhibition of Centrosome Separation after Ionizing Radiation^*

From the Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104

Activation of the G₂/M cell cycle checkpoint by DNA damage prevents cells from entering mitosis. Centrosome separation is initiated in G₂ phase and completed in M phase. This critical process for cell division is targeted by G₂/M checkpoint. Here we show that Plk1 signaling plays an important role in regulation of centrosome separation after DNA damage. Constitutively active Plk1 overrides the inhibition of centrosome separation induced by DNA damage. This inhibition is dependent on ATM, but not on Chk2 or Chk1. Nek2 is a key regulator of centrosome separation and is a target of Plk1 in blocking centrosome separation. We found that Plk1 can phosphorylate Nek2 in vitro and interacts with Nek2 in vivo. Down-regulation of Plk1 with RNA interference prevents Nek2-induced centrosome splitting. DNA damage is known to inhibit Plk1 activity. We propose that the DNA damage-induced inhibition of Plk1 leads to inhibition of Nek2 activity and thus prevents centrosome separation.

Received for publication, May 18, 2005 , and in revised form, September 1, 2005.

^* This work was supported by National Institutes of Health Grants CA 75138 and GM47439 (to R. J. M.) and National Institutes of Health Training Grant CA09677 (to W. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Radiation Oncology and Biology, 4A122 Academic Block, John Radcliffe Hospital, Oxford OX3 9DU. Tel.: 44(0)-1865-221-339; Fax: 44(0)-1865-220-993; E-mail: ruth.muschel{at}rob.ox.ac.uk.

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