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Mcm10 and And-1/CTF4 recruit DNA polymerase to chromatin for initiation of DNA replication

¹ Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA; ² Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

The MCM2-7 helicase complex is loaded on DNA replication origins during the G1 phase of the cell cycle to license the origins for replication in S phase. How the initiator primase–polymerase complex, DNA polymerase (pol ), is brought to the origins is still unclear. We show that And-1/Ctf4 (Chromosome transmission fidelity 4) interacts with Mcm10, which associates with MCM2-7, and with the p180 subunit of DNA pol . And-1 is essential for DNA synthesis and the stability of p180 in mammalian cells. In Xenopus egg extracts And-1 is loaded on the chromatin after Mcm10, concurrently with DNA pol , and is required for efficient DNA synthesis. Mcm10 is required for chromatin loading of And-1 and an antibody that disrupts the Mcm10–And-1 interaction interferes with the loading of And-1 and of pol , inhibiting DNA synthesis. And-1/Ctf4 is therefore a new replication initiation factor that brings together the MCM2-7 helicase and the DNA pol –primase complex, analogous to the linker between helicase and primase or helicase and polymerase that is seen in the bacterial replication machinery. The discovery also adds to the connection between replication initiation and sister chromatid cohesion.

[Keywords: And-1/CTF4; DNA replication; genome stability; cell cycle; DNA polymerase]

Received June 21, 2007; revised version accepted July 24, 2007.

⁴ Corresponding author.

E-MAIL ad8q{at}virginia.edu; FAX (434) 924-5069.

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

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1585607

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