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A more recent version of this article appeared on October 18, 2002
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M207226200v1
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Papers In Press, published online ahead of print August 15, 2002
J. Biol. Chem, 10.1074/jbc.M207226200
Submitted on July 18, 2002
Revised on August 14, 2002
Accepted on August 15, 2002

Protein phosphatase 2A regulates binding of Cdc45 to the pre-replication complex

Danny M. Chou, Paris Petersen, Johannes C. Walter, and Gernot Walter

Pathology-0612, University of California at San Diego, La Jolla, CA 92093-0612

Corresponding Author: GWalter{at}ucsd.edu

In eukaryotic cells, an ordered sequence of events leads to the initiation of DNA replication. During the G1 phase of the cell cycle, a pre-replication complex (pre-RC) consisting of ORC, Cdc6, Cdt1, and MCM2-7 is established at replication origins on the chromatin. At the G1/S transition, MCM10 and the protein kinases Cdc7-Dbf4 and Cdk2-cyclin E cooperate to recruit Cdc45 to the pre-RC, followed by origin unwinding, RPA binding, and recruitment of DNA polymerases. Using the soluble DNA replication system derived from Xenopus eggs, we demonstrate that immunodepletion of protein phosphatase 2A (PP2A) from egg extracts and inhibition of PP2A activity by okadaic acid abolish loading of Cdc45 to the pre-RC. Consistent with a defect in Cdc45 loading, origin unwinding and the loading of RPA and DNA polymerase alpha are also inhibited. Inhibition of PP2A has no effect on MCM10 loading and on Cdc7-Dbf4 or Cdk2 activity. The substrate of PP2A is neither a component of the pre-RC nor Cdc45. Instead, our data suggest that PP2A functions by dephosphorylating and activating a soluble factor that is required to recruit Cdc45 to the pre-RC. Furthermore, PP2A appears to counteract an unknown inhibitory kinase that phosphorylates and inactivates the same factor. Thus, the initiation of eukaryotic DNA replication is regulated at the level of Cdc45 loading by a combination of stimulatory and inhibitory phosphorylation events.


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