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Mec1 is one of multiple kinases that prime the Mcm2-7 helicase for phosphorylation by Cdc7.

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.

Pubmed ID: 21070963

Authors

  • Randell JC
  • Fan A
  • Chan C
  • Francis LI
  • Heller RC
  • Galani K
  • Bell SP

Journal

Molecular cell

Publication Data

November 12, 2010

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM052339
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acid Sequence
  • Amino Acids
  • Cell Cycle
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Minichromosome Maintenance Complex Component 7
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins
  • Phenotype
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins