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Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast

¹ Program in Molecular Biology, Sloan-Kettering Institute, New York, New York 10021, USA; ² Biochemistry, Cellular and Molecular Biology Program, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA

The DNA replication checkpoint is a complex signal transduction pathway, present in all eukaryotic cells, that functions to maintain genomic integrity and cell viability when DNA replication is perturbed. In Schizosaccharomyces pombe the major effector of the replication checkpoint is the protein kinase Cds1. Activation of Cds1 is known to require the upstream kinase Rad3 and the mediator Mrc1, but the biochemical mechanism of activation is not well understood. We report that the replication checkpoint is activated in two stages. In the first stage, Mrc1 recruits Cds1 to stalled replication forks by interactions between the FHA domain of Cds1 and specific phosphorylated Rad3 consensus sites in Mrc1. Cds1 is then primed for activation by Rad3-dependent phosphorylation. In the second stage, primed Cds1 molecules dimerize via phospho-specific interactions mediated by the FHA domains and are activated by autophosphorylation. This two-stage activation mechanism for the replication checkpoint allows for rapid activation with a high signal-to-noise ratio.

[Keywords: Cds1 autoactivation; Cds1 autophosphorylation; Cds1 dimerization; Mrc1 SQ cluster; Mrc1 TQ repeats; replication checkpoint]

Received December 30, 2005; revised version accepted February 9, 2006.

E-MAIL tkelly{at}mskcc.org; FAX (646) 422-2189.

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

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1406706

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