A yeast GSK-3 kinase Mck1 promotes Cdc6 degradation to inhibit DNA re-replication.

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dc.contributor.author Ikui, Amy E
dc.contributor.author Rossio, Valentina
dc.contributor.author Schroeder, Lea
dc.contributor.author Yoshida, Satoshi
dc.date.accessioned 2019-02-05T18:23:26Z
dc.date.available 2019-02-05T18:23:26Z
dc.date.issued 2012
dc.identifier.issn 1553-7404
dc.identifier.uri https://hdl.handle.net/10192/36477
dc.description.abstract Cdc6p is an essential component of the pre-replicative complex (pre-RC), which binds to DNA replication origins to promote initiation of DNA replication. Only once per cell cycle does DNA replication take place. After initiation, the pre-RC components are disassembled in order to prevent re-replication. It has been shown that the N-terminal region of Cdc6p is targeted for degradation after phosphorylation by Cyclin Dependent Kinase (CDK). Here we show that Mck1p, a yeast homologue of GSK-3 kinase, is also required for Cdc6 degradation through a distinct mechanism. Cdc6 is an unstable protein and is accumulated in the nucleus only during G1 and early S-phase in wild-type cells. In mck1 deletion cells, CDC6p is stabilized and accumulates in the nucleus even in late S phase and mitosis. Overexpression of Mck1p induces rapid Cdc6p degradation in a manner dependent on Threonine-368, a GSK-3 phosphorylation consensus site, and SCF(CDC4). We show evidence that Mck1p-dependent degradation of Cdc6 is required for prevention of DNA re-replication. Loss of Mck1 activity results in synthetic lethality with other pre-RC mutants previously implicated in re-replication control, and these double mutant strains over-replicate DNA within a single cell cycle. These results suggest that a GSK3 family protein plays an unexpected role in preventing DNA over-replication through Cdc6 degradation in Saccharomyces cerevisiae. We propose that both CDK and Mck1 kinases are required for Cdc6 degradation to ensure a tight control of DNA replication.
dc.format.extent 1 file
dc.language English
dc.language.iso eng
dc.relation.isversionof https://dx.doi.org/10.1371/journal.pgen.1003099
dc.rights Creative Commons Attribution 4.0 International License
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject Cell Cycle Proteins
dc.subject Cell Nucleus
dc.subject Cyclin-Dependent Kinases
dc.subject DNA Replication
dc.subject Glycogen Synthase Kinase 3
dc.subject Mitosis
dc.subject Proteolysis
dc.subject S Phase
dc.subject Saccharomyces cerevisiae
dc.subject Saccharomyces cerevisiae Proteins
dc.subject CDC6 protein, S cerevisiae
dc.subject Cell Cycle Proteins
dc.subject Saccharomyces cerevisiae Proteins
dc.subject Cyclin-Dependent Kinases
dc.subject Glycogen Synthase Kinase 3
dc.subject MCK1 protein, S cerevisiae
dc.title A yeast GSK-3 kinase Mck1 promotes Cdc6 degradation to inhibit DNA re-replication.
dc.type Article
dc.contributor.department Department of Biology
dc.relation.journal PLoS Genetics
dc.identifier.pmid 23236290
dc.identifier.pmcid PMC3516531


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