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Molecular and Cellular Biology, April 2007, p. 2625-2635, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.02072-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Artemis Links ATM to G₂/M Checkpoint Recovery via Regulation of Cdk1-Cyclin B

Liyi Geng,^1,2, Xiaoshan Zhang,^1, Shu Zheng,^2* and Randy J. Legerski^1*

Department of Cancer Genetics and The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030,¹ Cancer Institute, The Second Affiliated Hospital, Zhejiang University, 88 Jie-fang Road, Hangzhou, Zhejiang 310009, China²

Received 6 November 2006/ Returned for modification 2 December 2006/ Accepted 10 January 2007

Artemis is a phospho-protein that has been shown to have roles in V(D)J recombination, nonhomologous end-joining of double-strand breaks, and regulation of the DNA damage-induced G₂/M cell cycle checkpoint. Here, we have identified four sites in Artemis that are phosphorylated in response to ionizing radiation (IR) and show that ATM is the major kinase responsible for these modifications. Two of the sites, S534 and S538, show rapid phosphorylation and dephosphorylation, and the other two sites, S516 and S645, exhibit rapid and prolonged phosphorylation. Mutation of both of these latter two residues results in defective recovery from the G₂/M cell cycle checkpoint. This defective recovery is due to promotion by mutant Artemis of an enhanced interaction between unphosphorylated cyclin B and Cdk1, which in turn promotes inhibitory phosphorylation of Cdk1 by the Wee1 kinase. In addition, we show that mutant Artemis prevents Cdk1-cyclin B activation by causing its retention in the centrosome and inhibition of its nuclear import during prophase. These findings show that ATM regulates G₂/M checkpoint recovery through inhibitory phosphorylations of Artemis that occur soon after DNA damage, thus setting a molecular switch that, hours later upon completion of DNA repair, allows activation of the Cdk1-cyclin B complex. These findings thus establish a novel function of Artemis as a regulator of the cell cycle in response to DNA damage.

Published ahead of print on 22 January 2007.

L.G. and X.Z. contributed equally to this work.