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J. Biol. Chem., Vol. 283, Issue 28, 19176-19183, July 11, 2008

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Regulation of Intra-S Phase Checkpoint by Ionizing Radiation (IR)-dependent and IR-independent Phosphorylation of SMC3^*

Hao Luo¹, Yehua Li¹, Jung-Jung Mu¹, Jinglan Zhang, Toru Tonaka, Yasuo Hamamori, Sung Yun Jung, Yi Wang, and Jun Qin²

From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Department of Molecular and Cellular Biology and the Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Structure maintenance of chromosome 1 (SMC1) is phosphorylated by ataxia telangiectasia-mutated (ATM) in response to ionizing radiation (IR) to activate intra-S phase checkpoint. A role of CK2 in DNA damage response has been implicated in many previous works, but the molecular mechanism for its activation is not clear. In the present work, we report that SMC3 is phosphorylated at Ser-1067 and Ser-1083 in vivo. Ser-1083 phosphorylation is IR-inducible, depends on ATM and Nijmegen breakage syndrome 1 (NBS1), and is required for intra-S phase checkpoint. Interestingly, Ser-1067 phosphorylation is constitutive and is not induced by IR but also affects intra-S phase checkpoint. Phosphorylation of Ser-1083 is weakened in cells expressing S1067A mutant, suggesting interplay between Ser-1067 and Ser-1083 phosphorylation in DNA damage response. Consistently, small interfering RNA knockdown of CK2 leads to attenuated phosphorylation of Ser-1067 as well as intra-S phase checkpoint defect. Our data provide evidence that phosphorylation of a core cohesin subunit SMC3 by ATM plays an important role in DNA damage response and suggest that a constitutive phosphorylation by CK2 may affect intra-S phase checkpoint by modulating SMC3 phosphorylation by ATM.

Received for publication, March 24, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA98500 (to J. Q.) and DAMD W81XWH 04-1-0437 (to Y. W.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and a supplemental figure.

This article was selected as a Paper of the Week.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 713-798-1507; Fax: 713-798-1625; E-mail: jqin{at}bcm.tmc.edu.

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