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Cdk1-mediated phosphorylation of Cdc7 suppresses DNA re-replication

Title
Cdk1-mediated phosphorylation of Cdc7 suppresses DNA re-replication
Authors
Knockleby, J[Knockleby, James]Kim, BJ[Kim, Byung Ju]Mehta, A[Mehta, Avani]Lee, H[Lee, Hoyun]
Issue Date
2016
Citation
Cell Cycle, 15(11), 1494-1505
Type
Article
Article Type
Article
Keywords
Cdc7Cdc7 KinaseCDK1 ProteinCell CycleCell Cycle G2 Phasedbf4 KinaseDDKDephosphorylationDissociationDNA ReplicationEnzyme PhosphorylationMitosisPhosphorylationPhosphotransferasePrometaphaseProtein PhosphorylationUnclassified Drug
ISSN
1538-4101
Abstract
To maintain genetic stability, the entire mammalian genome must replicate only once per cell cycle. This is largely achieved by strictly regulating the stepwise formation of the pre-replication complex (pre-RC), followed by the activation of individual origins of DNA replication by Cdc7/Dbf4 kinase. However, the mechanism how Cdc7 itself is regulated in the context of cell cycle progression is poorly understood. Here we report that Cdc7 is phosphorylated by a Cdk1-dependent manner during prometaphase on multiple sites, resulting in its dissociation from origins. In contrast, Dbf4 is not removed from origins in prometaphase, nor is it degraded as cells exit mitosis. Our data thus demonstrates that constitutive phosphorylation of Cdc7 at Cdk1 recognition sites, but not the regulation of Dbf4, prevents the initiation of DNA replication in normally cycling cells and under conditions that promote re-replication in G2/M. As cells exit mitosis, PP1α associates with and dephosphorylates Cdc7. Together, our data support a model where Cdc7 (de)phosphorylation is the molecular switch for the activation and inactivation of DNA replication in mitosis, directly connecting Cdc7 and PP1α/Cdk1 to the regulation of once-per-cell cycle DNA replication in mammalian cells. © 2016 Taylor & Francis.
URI
http://hdl.handle.net/20.500.11750/2625
DOI
10.1080/15384101.2016.1176658
Publisher
Taylor and Francis Inc.
Files:
There are no files associated with this item.
Collection:
ETC1. Journal Articles


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