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Papers In Press, published online ahead of print July 13, 2001
Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511
Corresponding Author: yukio{at}libra.ls.m-kagaku.co.jp
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/cyclinA in vitro. Here, we further examined the interplay between Mcm4,6,7 complex and cyclin-dependent kinases, and determined the sites required for the phosphorylation of Mcm4. Six Ser and Thr residues in total were required for the phosphorylation. Inhibition of Mcm4,6,7 helicase activity by Cdk2/cyclinA 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 at 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.
J. Biol. Chem, 10.1074/jbc.M104480200
Submitted on May 17, 2001
Revised on July 9, 2001
Accepted on July 12, 2001
Phosphorylation of Mcm4 at specific sites by cyclin-dependent kinase leads to loss of Mcm4,6,7 helicase activity
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