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J. Biol. Chem., Vol. 281, Issue 46, 35425-35435, November 17, 2006

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Spy1 Expression Prevents Normal Cellular Responses to DNA Damage

INHIBITION OF APOPTOSIS AND CHECKPOINT ACTIVATION^*

Randy F. Gastwirt, Daniela A. Slavin, Christopher W. McAndrew, and Daniel J. Donoghue^¶1

From the Biomedical Sciences Program, Department of Chemistry and Biochemistry, and ^¶Moores University of California San Diego Cancer Center, University of California San Diego, La Jolla, California 92093-0367

Spy1 is the originally identified member of the Speedy/Ringo family of vertebrate cell cycle regulators, which can control cell proliferation and survival through the atypical activation of cyclin-dependent kinases. Here we report a role for Spy1 in apoptosis and checkpoint activation in response to UV irradiation. Using an inducible system allowing for regulated expression of Spy1, we show that Spy1 expression prevents activation of caspase-3 and suppresses apoptosis in response to UV irradiation. Spy1 expression also allows for UV irradiation-resistant DNA synthesis and permits cells to progress into mitosis, as demonstrated by phosphorylation on histone H3, indicating that Spy1 expression can inhibit the S-phase/replication and G₂/M checkpoints. We demonstrate that Spy1 expression inhibits phosphorylation of Chk1, RPA, and histone H2A.X, which may directly contribute to the decrease in apoptosis and checkpoint bypass. Furthermore, mutation of the conserved Speedy/Ringo box, known to mediate interaction with CDK2, abrogates the ability of Spy1 to inhibit apoptosis and the phosphorylation of Chk1 and RPA. The data presented indicate that Spy1 expression allows cells to evade checkpoints and apoptosis and suggest that Spy1 regulation of CDK2 is important for the response to DNA damage.

Received for publication, May 17, 2006 , and in revised form, August 10, 2006.

^* This work was supported by NCI, National Institutes of Health, Ruth L. Kirschstein National Research Service Award T32 CA009523 [GenBank] (to R. G.). 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: University of California San Diego, Dept. of Chemistry and Biochemistry, 9500 Gilman Dr., La Jolla, CA 92093-0367. Tel.: 858-534-2463; Fax: 858-534-7481; E-mail: ddonoghue{at}ucsd.edu.

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