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Cyclin-Dependent Kinase 2–Dependent Phosphorylation of ATRIP Regulates the G₂-M Checkpoint Response to DNA Damage

¹ Department of Biochemistry and ² Mass Spectrometry Research Center, Vanderbilt University, Nashville, Tennessee

Requests for reprints: David Cortez, Department of Biochemistry, Vanderbilt University, 613 Light Hall, 23rd Pierce Avenue, Nashville, TN 37232. Phone: 615-322-8547; Fax: 615-343-0704; E-mail: david.cortez{at}vanderbilt.edu.

The ATR-ATRIP kinase complex regulates cellular responses to DNA damage and replication stress. Mass spectrometry was used to identify phosphorylation sites on ATR and ATRIP to understand how the kinase complex is regulated by post-translational modifications. Two novel phosphorylation sites on ATRIP were identified, S224 and S239. Phosphopeptide-specific antibodies to S224 indicate that it is phosphorylated in a cell cycle–dependent manner. S224 matches a consensus site for cyclin-dependent kinase (CDK) phosphorylation and is phosphorylated by CDK2-cyclin A in vitro. S224 phosphorylation in cells is sensitive to CDK2 inhibitors. Mutation of S224 to alanine causes a defect in the ATR-ATRIP–dependent maintenance of the G₂-M checkpoint to ionizing and UV radiation. Thus, ATRIP is a CDK2 substrate, and CDK2-dependent phosphorylation of S224 regulates the ability of ATR-ATRIP to promote cell cycle arrest in response to DNA damage. [Cancer Res 2007;67(14):6685–90]

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