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DNA Damage and Cellular Stress Responses

Polo-Like Kinase 1 Inactivation Following Mitotic DNA Damaging Treatments Is Independent of Ataxia Telangiectasia Mutated Kinase¹

¹ Basic Research Program, Science Applications International Corporation-Frederick, Inc., ² Experimental and Computational Biology and ³ Laboratory of Cancer Prevention, Center of Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland; and
⁴ Gerontology Research Center, National Institute on Aging, Baltimore, Maryland

Requests for reprints: Douglas K. Ferris, Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Building 567, Room 218, Frederick, MD 21702. Phone: (301) 846-1429; Fax: (301) 846-6641. E-mail: ferris{at}ncifcrf.gov

Polo-like kinase 1 (Plk1) is an important regulator of several events during mitosis. Recent reports show that Plk1 is involved in both G₂ and mitotic DNA damage checkpoints. Ataxia telangiectasia mutated kinase (ATM) is an important enzyme involved in G₂ phase cell cycle arrest following interphase DNA damage, and inhibition of Plk1 by DNA damage during G₂ occurs in an ATM-/ATM-Rad3–related kinase (ATR)–dependent fashion. However, it is unclear how Plk1 is regulated in response to M phase DNA damage. We found that treatment of mitotic cells with DNA damaging agents inhibits Plk1 activity primarily through dephosphorylation of Plk1, which occurred in both p53 wild-type and mutant cells. Inhibition of Plk1 is not prevented by caffeine pretreatment that inhibits ATM activity and also occurs in ATM mutant cell lines. Furthermore, ATM mutant cell lines, unlike wild-type cells, fail to arrest after mitotic DNA damaging treatments. The phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, reduces Plk1 dephosphorylation following mitotic DNA damaging treatments, suggesting that the PI3K pathway may be involved in regulating Plk1 activity. Earlier studies showed that inhibition of Plk1 by G₂ DNA damage occurs in an ATM-dependent fashion. Our results extend the previous studies by showing that ATM is not required for dephosphorylation and inhibition of Plk1 activity following mitotic DNA damage, and also suggest that Plk1 is not a principal regulator or mediator of the mitotic DNA damage response.

Key Words: polo-like kinase 1 (Plk1) • Mitotic DNA damage • ataxia telangiectasia mutated kinase (ATM) • Dephosphorylation • phosphatidylinositol 3-kinase (PI3K)