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J. Biol. Chem., Vol. 282, Issue 4, 2729-2740, January 26, 2007

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Human Tim/Timeless-interacting Protein, Tipin, Is Required for Efficient Progression of S Phase and DNA Replication Checkpoint^*

From the Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan

Tipin was originally isolated as a protein interacting with Timeless/Tim1/Tim (Tim), which is known to be involved in both circadian rhythm and cell cycle checkpoint regulation. The endogenous Tim and Tipin proteins in human cells, interacting through the N-terminal segment of each molecule, form a complex throughout the cell cycle. Tipin and Tim are expressed in the interphase nuclei mostly at constant levels during the cell cycle, and small fractions are recovered in the chromatin-enriched fractions during S phase. Depletion of endogenous Tipin results in reduced growth rate, and this may be due in part to inefficient progression of S phase and DNA synthesis. Knockdown of Tipin induces radioresistant DNA synthesis and inhibits phosphorylation of Chk1 kinase caused by replication stress, as was observed with that of Tim. Knockdown of Tipin or Tim results in reduced protein level and relocation to the cytoplasm of the respective binding partner, suggesting that the complex formation may be required for stabilization and nuclear accumulation of both proteins. Furthermore, both Tipin and Tim may facilitate the accumulation of Claspin in the nuclei under replication stress, whereas nuclear localization of Tipin and Tim is unaffected by Claspin. Our results indicate that mammalian Tipin is a checkpoint mediator that cooperates with Tim and may regulate the nuclear relocation of Claspin in response to replication checkpoint.

Received for publication, June 12, 2006 , and in revised form, November 13, 2006.

^* This work is supported by grants-in-aid for scientific research "A" and scientific research on priority areas (to H. M.) and scientific research "C" (to N. Y.) from the Ministry of Education, Science, Sports and Culture, and the Astellas Foundation for Research on Metabolic Disorders (to H. M.). 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: Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Hon-komagome, Bunkyo-ku, Tokyo 113-8613, Japan. Tel.: 81-3-5685-2264; Fax: 81-3-5685-2932; E-mail: hmasai{at}rinshoken.or.jp.

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