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Molecular and Cellular Biology, May 2009, p. 2609-2621, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01277-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Polo-Like Kinase 1 Depletion Induces DNA Damage in Early S Prior to Caspase Activation{triangledown} ,{dagger}

Hyungshin Yim* and Raymond L. Erikson

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138

Received 12 August 2008/ Returned for modification 22 September 2008/ Accepted 4 March 2009

Polo-like kinase 1 (Plk1) plays several roles in mitosis, and it has been suggested to have a role in tumorigenesis. We have previously reported that Plk1 depletion results in cell death in cancer cells, whereas normal cells survive similar depletion. However, Plk1 depletion together with p53 depletion induces cell death in normal cells as well. This communication presents evidence on the sequence of events that leads to cell death in cancer cells. DNA damage is detected at the first S phase following Plk1 depletion and is more severe in Plk1-depleted p53-null cancer cells. As a consequence of Plk1 depletion using lentivirus-based small interfering RNA techniques, prereplicative complex (pre-RC) formation is disrupted at the G1/S transition, and DNA synthesis is reduced during S phase of the first cycle after depletion. The levels of geminin, an inhibitor of DNA pre-RC, and Emi1, an inhibitor of anaphase-promoting complex/cyclosome, are elevated in Plk1-depleted cells. The rate of cell cycling is slower in Plk1-depleted cells than in control cells when synchronized by serum starvation. Plk1 depletion results in disrupted DNA pre-RC formation, reduced DNA synthesis, and DNA damage before cells display severe mitotic catastrophe or apoptosis. Our data suggest that Plk1 is required for cell cycle progression not only in mitosis but also for DNA synthesis, maintenance of DNA integrity, and prevention of cell death.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Ave., Cambridge, MA 02138. Phone: (617) 495-5386. Fax: (617) 495-0681. E-mail: hyim{at}fas.harvard.edu

{triangledown} Published ahead of print on 16 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2009, p. 2609-2621, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01277-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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