Mec1 Is One of Multiple Kinases that Prime the Mcm2-7 Helicase for Phosphorylation by Cdc7
Author(s)Randell, John C.W.; Chan, Clara Sophia; Francis, Laura I.; Heller, Ryan C.; Bell, Stephen P.; Galani, Kyriakitsa; Fan, Andy, 1976-; ... Show more Show less
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Activation of the eukaryotic replicative DNA helicase, the Mcm2-7 complex, requires phosphorylation by Cdc7/Dbf4 (Dbf4-dependent kinase or DDK), which, in turn, depends on prior phosphorylation of Mcm2-7 by an unknown kinase (or kinases). We identified DDK phosphorylation sites on Mcm4 and Mcm6 and found that phosphorylation of either subunit suffices for cell proliferation. Importantly, prior phosphorylation of either S/T-P or S/T-Q motifs on these subunits is required for DDK phosphorylation of Mcm2-7 and for normal S phase passage. Phosphomimetic mutations of DDK target sites bypass both DDK function and mutation of the priming phosphorylation sites. Mrc1 facilitates Mec1 phosphorylation of the S/T-Q motifs of chromatin-bound Mcm2-7 during S phase to activate replication. Genetic interactions between priming site mutations and MRC1 or TOF1 deletion support a role for these modifications in replication fork stability. These findings identify regulatory mechanisms that modulate origin firing and replication fork assembly during cell cycle progression.
DepartmentMassachusetts Institute of Technology. Department of Biology
Randell, John C.W., Andy Fan, Clara Chan, Laura I. Francis, Ryan C. Heller, Kyriaki Galani, and Stephen P. Bell. “Mec1 Is One of Multiple Kinases that Prime the Mcm2-7 Helicase for Phosphorylation by Cdc7.” Molecular Cell 40, no. 3 (November 2010): 353-363. Copyright © 2010 Elsevier Inc.
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