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J. Biol. Chem., Vol. 277, Issue 36, 33049-33057, September 6, 2002
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,
From the Department of Biological Chemistry and Molecular
Pharmacology, Harvard Medical School, Boston, Massachusetts 02115
The MCM2-7 complex is believed to function as
the eukaryotic replicative DNA helicase. It is recruited to chromatin
by the origin recognition complex (ORC), Cdc6, and Cdt1, and it is
activated at the G1/S transition by Cdc45 and the
protein kinases Cdc7 and Cdk2. Paradoxically, the number of
chromatin-bound MCM complexes greatly exceeds the number of bound ORC
complexes. To understand how the high MCM2-7:ORC ratio comes about, we
examined the binding of these proteins to immobilized linear DNA
fragments in Xenopus egg extracts. The minimum length of
DNA required to recruit ORC and MCM2-7 was ~80 bp, and the
MCM2-7:ORC ratio on this fragment was ~1:1. With longer DNA
fragments, the MCM2-7:ORC ratio increased dramatically, indicating
that MCM complexes normally become distributed over a large region of
DNA surrounding ORC. Only a small subset of the chromatin-bound MCM2-7
complexes recruited Cdc45 at the onset of DNA replication, and unlike
Cdc45, MCM2-7 was not limiting for DNA replication. However, all the
chromatin-bound MCM complexes may be functional, because they were
phosphorylated in a Cdc7-dependent fashion, and because
they could be induced to support Cdk2-dependent Cdc45
loading. The data suggest that in Xenopus egg extracts, origins of replication contain multiple, distributed,
initiation-competent MCM2-7 complexes.
Present address: Dept. of Geological Sciences, University of
Texas, Austin, TX 78712.
§
To whom correspondence should be addressed: Dept. of Biological
Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115. Tel.: 617-432-4799; Fax: 617-738-0516;
E-mail: johannes_walter@hms.harvard.edu.
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