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Cdc7–Drf1 kinase links chromosome cohesion to the initiation of DNA replication in Xenopus egg extracts

¹ Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA; ² Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

To establish functional cohesion between replicated sister chromatids, cohesin is recruited to chromatin before S phase. Cohesin is loaded onto chromosomes in the G1 phase by the Scc2–Scc4 complex, but little is known about how Scc2–Scc4 itself is recruited to chromatin. Using Xenopus egg extracts as a vertebrate model system, we showed previously that the chromatin association of Scc2 and cohesin is dependent on the prior establishment of prereplication complexes (pre-RCs) at origins of replication. Here, we report that Scc2–Scc4 exists in a stable complex with the Cdc7–Drf1 protein kinase (DDK), which is known to bind pre-RCs and activate them for DNA replication. Immunodepletion of DDK from Xenopus egg extracts impairs chromatin association of Scc2–Scc4, a defect that is reversed by wild-type, but not catalytically inactive DDK. A complex of Scc4 and the N terminus of Scc2 is sufficient for chromatin loading of Scc2–Scc4, but not for cohesin recruitment. These results show that DDK is required to tether Scc2–Scc4 to pre-RCs, and they underscore the intimate link between early steps in DNA replication and cohesion.

[Keywords: Cdc7–Drf1; DNA replication; Xenopus; cohesin; cohesion; Scc2–Scc4]

Received April 10, 2008; revised version accepted May 23, 2008.

⁴ Corresponding authors.

E-MAIL johannes_walter{at}hms.harvard.edu; FAX (617) 738-0516

⁵ E-MAIL tatsuro_takahashi{at}bio.sci.osaka-u.ac.jp; FAX 81-6-6850-5440.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1683308.

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