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J. Biol. Chem., Vol. 278, Issue 27, 24644-24650, July 4, 2003

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Identification of MCM4 as a Target of the DNA Replication Block Checkpoint System^*

Yukio Ishimi  , Yuki Komamura-Kohno , Hyun-Ju Kwon  ¶, Kouichi Yamada || and Makoto Nakanishi **

From the Biomolecular and Technology Department, Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, ^||National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, and the ^**Department of Biochemistry and Cell Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan

Inhibition of the progression of DNA replication prevents further initiation of DNA replication and allows cells to maintain arrested replication forks, but the proteins that are targets of the replication checkpoint system remain to be identified. We report here that human MCM4, a subunit of the putative DNA replicative helicase, is extensively phosphorylated in HeLa cells when they are incubated in the presence of inhibitors of DNA synthesis or are exposed to UV irradiation. The data presented here indicate that the consecutive actions of ATR-CHK1 and CDK2 kinases are involved in this phosphorylation in the presence of hydroxyurea. The phosphorylation sites in MCM4 were identified using specific anti-phosphoantibodies. Based on results that showed that the DNA helicase activity of the MCM4-6-7 complex is negatively regulated by CDK2 phosphorylation, we suggest that the phosphorylation of MCM4 in the checkpoint control inhibits DNA replication, which includes blockage of DNA fork progression, through inactivation of the MCM complex.

Received for publication, December 30, 2002 , and in revised form, April 18, 2003.

^* This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Technology, Sports and Culture, Japan. 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.

^¶ Present address: Dept. of Life Science & Biotechnology, College of Natural Science, Dong-Eui University, Korea.

To whom correspondence should be addressed. Tel.: 81-42-724-6266; Fax: 81-42-724-6314; E-mail: yukio{at}libra.ls.m-kagaku.co.jp.

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