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J. Biol. Chem., Vol. 283, Issue 10, 6209-6221, March 7, 2008

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Plk1-dependent Phosphorylation Regulates Functions of DNA Topoisomerase II in Cell Cycle Progression^*

From the Department of Biochemistry and the Cancer Center, Purdue University, West Lafayette, Indiana 47907

Plk1 (Polo-like kinase 1) has been documented as a critical regulator of many mitotic events. However, increasing evidence supports the notion that Plk1 might also have functions outside of mitosis. Using biochemical fractionation and RNA interference approaches, we found that Plk1 was required for both G₁/S and G₂/M phases and that DNA topoisomerase II (topoII) was a potential target for Plk1 in both interphase and mitosis. Plk1 phosphorylates Ser¹³³⁷ and Ser¹⁵²⁴ of topoII. Overexpression of an unphosphorylatable topoII mutant led to S phase arrest, suggesting that Plk1-associated phosphorylation first occurs in S phase. Moreover, overexpression of the unphosphorylatable topoII mutant activated the ATM/R-dependent DNA damage checkpoint, probably due to reduced catalytic activity of topoII, and resulted in accumulation of catenated DNA. Finally, we showed that wild type topoII, but not the unphosphorylatable mutant, was able to rescue topoII depletion-induced defects in sister chromatid segregation, indicating that Plk1-associated phosphorylation is essential for the functions of topoII in mitosis.

Received for publication, November 1, 2007 , and in revised form, December 28, 2007.

^* 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: Dept. of Biochemistry, Purdue University, 175 S. University St., West Lafayette, IN 47907. Tel.: 765-496-3764; Fax: 765-494-7897; E-mail: liu8{at}purdue.edu.

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