Journal
CELL DEATH & DISEASE
Volume 11, Issue 4, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-020-2493-1
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Funding
- Ohio State University Comprehensive Cancer Center/Department of Radiation Oncology start-up funds
- American Cancer Society [RSG-18-066-01-TBG]
- NIH [R01 GM112895, R01 GM108743, R03CA227206]
- National Institutes of Health [1S10RR031537-01, P30 CA016058]
- Ohio State University Comprehensive Cancer Center
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APC/C-Cdh1 is a ubiquitin ligase with roles in numerous diverse processes, including control of cellular proliferation and multiple aspects of the DNA damage response. Precise regulation of APC/C-Cdh1 activity is central to efficient cell-cycle progression and cellular homeostasis. Here, we have identified Cdh1 as a direct substrate of the replication stress checkpoint effector kinase Chk1 and demonstrate that Chk1-mediated phosphorylation of Cdh1 contributes to its recognition by the SCF beta TRCP ubiquitin ligase, promotes efficient S-phase entry, and is important for cellular proliferation during otherwise unperturbed cell cycles. We also find that prolonged Chk1 activity in late S/G2 inhibits Cdh1 accumulation. In addition to promoting control of APC/C-Cdh1 activity by facilitating Cdh1 destruction, we find that Chk1 also antagonizes activity of the ligase by perturbing the interaction between Cdh1 and the APC/C. Overall, these data suggest that the rise and fall of Chk1 activity contributes to the regulation of APC/C-Cdh1 activity that enhances the replication process.
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