Eukaryotic cells duplicate their chromosomes. Errors in the DNA replication control could lead to chromosome instability. Our long-term goal is to understand the molecular mechanism of DNA replication control in eukaryotes. Cdc6p is a key DNA replication component from yeast to humans. Our preliminary results showed that yeast GSK-3 kinase (Mck1p) targets DNA replication factor Cdc6p for degradation, which in turn inhibits DNA re-replication. It is known that N-terminal region of Cdc6 is phosphorylated by Cyclin/CDK complex for its degradation after the origin is licensed. We will study the novel Cdc6p degradation mechanism controlled by Mck1p kinase to inhibit DNA re- replication. In this proposal, three aims will test my hypothesis if a sequential phosphorylation of Cdc6p by Cdk1 and GSK3 controls the timing of Cdc6p degradation.
Aim1 will test if Cdc6p is directly phosphorylated by Mck1 kinase, and Mck1-depedent Cdc6 degradation is mediated through SCFCDC4 complex.
Aim2 will test the possibility that Mck1p targets Cdc6p in a distinct mechanism from CDK.
Aim3 will test if the phosphorylation of Cdc6 by CDK is a pre-requisite for phosphorylation by Mck1p. Cdc6p and GSK-3 kinase are conserved from yeast to humans. The results obtained from this study can be applied to understand the molecular mechanism of Cdc6 degradation by GSK-3 kinase in higher eukaryotes. The accurate DNA replication control is a critical step to avoid chromosome instability, and it is important to understand since the chromosome instability is a hallmark of tumorigenesis.

Public Health Relevance

A failure of the replication inhibition control results in DNA re-replication which will trigger chromosome instability which is a hallmark of tumorigenesis. Therefore, it is important to study the mechanism of DNA replication control in eukaryotes to understand the molecular mechanism of tumorigenesis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Continuance Award (SC3)
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Special Emphasis Panel (ZGM1-TWD-9 (SC))
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Krasnewich, Donna M
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Brooklyn College
Schools of Arts and Sciences
New York
United States
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Kono, Keiko; Ikui, Amy E (2017) A new cell cycle checkpoint that senses plasma membrane/cell wall damage in budding yeast. Bioessays 39:
Kono, Keiko; Al-Zain, Amr; Schroeder, Lea et al. (2016) Plasma membrane/cell wall perturbation activates a novel cell cycle checkpoint during G1 in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 113:6910-5
Al-Zain, Amr; Schroeder, Lea; Sheglov, Alina et al. (2015) Cdc6 degradation requires phosphodegron created by GSK-3 and Cdk1 for SCFCdc4 recognition in Saccharomyces cerevisiae. Mol Biol Cell 26:2609-19