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RESEARCH PAPER
1 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 2 The Rockefeller University, New York, New York 10021, USA
Cyclin-dependent kinases are critical regulators of eukaryotic DNA replication. We show that the S-phase cyclin Clb5 binds stably and directly to the origin recognition complex (ORC). This interaction is mediated by an "RXL" target sequence, or "Cy" motif, in the Orc6 subunit that is recognized by the "hydrophobic patch" region on Clb5. The Clb5-Orc6 interaction requires replication initiation, and is maintained throughout the remainder of S phase and into M phase. Eliminating the Clb5-Orc6 interaction has no effect on initiation of replication but instead sensitizes cells to lethal overreplication. We propose that Clb5 binding to ORC provides an origin-localized replication control switch that specifically prevents reinitiation at replicated origins.
[Keywords: Cell cycle control; DNA replication; cyclin-dependent kinase; origin recognition complex; genomic stability; re-replication]
Received October 23, 2003; revised version accepted March 18, 2004.
Supplemental material is available at http://www.genesdev.org.
3 Present address: Department of Biochemistry and Biophysics, University of California at San Francisco, 600 16th St., San Francisco, CA 94143-2200, USA
6 These authors contributed equally to this work.
4 Present address: Tularik Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA
5 Present address: Stony Brook SUNY School of Medicine, Stony Brook, NY 11794, USA.
7 Corresponding authors. These authors contributed equally to this work.
8 E-MAIL spbell{at}mit.edu; FAX (617) 253-4043.
9 E-MAIL fcross{at}mail.rockefeller.edu; FAX (212) 327-7193.
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