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J. Biol. Chem., Vol. 276, Issue 37, 34428-34433, September 14, 2001
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and
From the Mitsubishi Kagaku Institute of Life Sciences,
11 Minamiooya, Machida, Tokyo 194-8511, Japan
Mcm proteins that play an essential role in
eukaryotic DNA replication are phosphorylated in vivo, and
cyclin-dependent protein kinase is at least in part
responsible for the phosphorylation of Mcm4. Our group reported
that the DNA helicase activity of Mcm4,6,7 complex, which may be
involved in initiation of DNA replication, is inhibited following
phosphorylation by Cdk2/cyclin A in vitro. Here, we further
examined the interplay between mouse Mcm4,6,7 complex and
cyclin-dependent kinases and determined the sites required
for the phosphorylation of Mcm4. Six Ser and Thr residues, in all, were
required for the phosphorylation. Inhibition of Mcm4,6,7 helicase
activity by Cdk2/cyclin A was largely relieved by introducing mutations
in these residues of Mcm4. Anti-phosphothreonine antibodies raised
against one of these sites reacted with Mcm4 prepared from HeLa cells
at mitotic phase but did not bind to those at G1 and G1/S, suggesting that this site is mainly phosphorylated in
the mitotic phase. Mcm4,6,7 complex purified from HeLa cells at the mitotic phase exhibited a low level of DNA helicase activity, compared
with the complexes prepared from cells at other phases. These
results suggest that phosphorylation of Mcm4 at specific sites leads to
loss of Mcm4,6,7 DNA helicase activity.
To whom correspondence should be addressed. Tel.: 81-42-724-6266;
Fax: 81-42-724-6314; E-mail: yukio@libra.ls.m-kagaku.co.jp.
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