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J. Biol. Chem., Vol. 282, Issue 8, 5346-5355, February 23, 2007

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Tel2 Is Required for Activation of the Mrc1-mediated Replication Checkpoint^*

From the Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kitashirakawaoiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan

Proteins belonging to the Tel2/Rad-5/Clk-2 family are conserved among eukaryotes and are involved in various cellular processes, such as cell proliferation, telomere maintenance, the biological clock, and the DNA damage checkpoint. However, the molecular mechanisms underlying the functions of these molecules remain largely unclear. Here we report that in the fission yeast, Schizosaccharomyces pombe, Tel2 is required for efficient phosphorylation of Mrc1, a mediator of DNA replication checkpoint signaling, and for activation of Cds1, a replication checkpoint kinase, when DNA replication is blocked by hydroxyurea. In fact, Tel2 is required for survival of replication fork arrest and for the replication checkpoint in cells lacking Chk1, another checkpoint kinase the role of which overlaps that of Cds1 in cell cycle arrest by replication block. In addition, Tel2 plays important roles in entry into S phase and in genome stability. Tel2 is essential for vegetative cell growth, and the tel2 strain accumulated cells with 1C DNA content after germination. In the absence of hydroxyurea, Tel2 is vital in the mutant lacking Swi1, a component of the replication fork protection complex, and multiple Rad22 DNA repair foci were frequently observed in Tel2-repressed swi1 cells especially at S phase. In contrast, the cds1swi1 mutant did not show such lethality. These results indicate that S. pombe Tel2 plays important roles in the Mrc1-mediated replication checkpoint as well as in the Cds1-independent regulation of genome integrity.

Received for publication, August 4, 2006 , and in revised form, December 21, 2006.

^* 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 Fig. S1.

¹ Supported by a COE grant, grants-in-aid for cancer research, and grants-in-aid for scientific research (S) from the Ministry of Education, Culture, Sports, Science, and Technology.

² Supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology. To whom correspondence should be addressed: Dept. of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kitashirakawaoiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan. Tel.: 81-75-753-4196; Fax: 81-75-753-4197; E-mail: jkanoh{at}lif.kyoto-u.ac.jp.

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