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Molecular and Cellular Biology, July 2004, p. 5875-5886, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5875-5886.2004

Role for Cdk1 (Cdc2)/Cyclin A in Preventing the Mammalian Origin Recognition Complex's Largest Subunit (Orc1) from Binding to Chromatin during Mitosis

Cong-jun Li,1 Alex Vassilev,2 and Melvin L. DePamphilis2*

Growth Biology Laboratory, Animal and Natural Resources Institute, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, Maryland 20705,1 National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 208922

Received 10 September 2003/ Returned for modification 7 January 2004/ Accepted 23 March 2004

The eukaryotic origin recognition complex (ORC) selects the genomic sites where prereplication complexes are assembled and DNA replication begins. In proliferating mammalian cells, ORC activity appears to be regulated by reducing the affinity of the Orc1 subunit for chromatin during S phase and then preventing reformation of a stable ORC-chromatin complex until mitosis is completed and a nuclear membrane is assembled. Here we show that part of the mechanism by which this is accomplished is the selective association of Orc1 with Cdk1 (Cdc2)/cyclin A during the G2/M phase of cell division. This association accounted for the appearance in M-phase cells of hyperphosphorylated Orc1 that was subsequently dephosphorylated during the M-to-G1 transition. Moreover, inhibition of Cdk activity in metaphase cells resulted in rapid binding of Orc1 to chromatin. However, chromatin binding was not mediated through increased affinity of Orc1 for Orc2, suggesting that additional events are involved in the assembly of functional ORC-chromatin sites. These results reveal that the same cyclin-dependent protein kinase that initiates mitosis in mammalian cells also concomitantly inhibits assembly of functional ORC-chromatin sites.

* Corresponding author. Mailing address: National Institute of Child Health and Human Development, Building 6/416, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-2753. Phone: (301) 402-8234. Fax: (301) 480-9354. E-mail: depamphm{at}mail.nih.gov.

Molecular and Cellular Biology, July 2004, p. 5875-5886, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5875-5886.2004




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