Chk1-mediated phosphorylation of Cdh1 promotes the SCFβTRCP-dependent degradation of Cdh1 during S-phase and efficient cell-cycle progression

Debjani Pal; Adrian E. Torres; Benjamin R. Stromberg; Abbey L. Messina; Andrew S. Dickson; Kuntal De; Belinda Willard; Monica Venere; Matthew K. Summers

doi:10.1038/s41419-020-2493-1

Chk1-mediated phosphorylation of Cdh1 promotes the SCF^βTRCP-dependent degradation of Cdh1 during S-phase and efficient cell-cycle progression

Debjani Pal, Adrian E. Torres, Benjamin R. Stromberg, Abbey L. Messina, Andrew S. Dickson, Kuntal De, Belinda Willard, Monica Venere, Matthew K. Summers

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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^βTRCP 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.

Original language	English
Article number	298
Journal	Cell Death and Disease
Volume	11
Issue number	4
DOIs	https://doi.org/10.1038/s41419-020-2493-1
State	Published - Apr 1 2020

Funding

This work was supported by The Ohio State University Comprehensive Cancer Center/Department of Radiation Oncology start-up funds to MV and MKS, American Cancer Society grant RSG-18-066-01-TBG and NIH grant R03CA227206 to MV, and NIH grants R01 GM112895 and R01 GM108743 to MKS. The Orbitrap Elite instrument of the Lerner Research Institute Proteomics Core at the Cleveland Clinic Foundation was purchased via an National Institutes of Health shared instrument grant, 1S10RR031537-01. Research reported in the publication was supported by The Ohio State University Comprehensive Cancer Center and the National Institutes of Health under grant number P30 CA016058. The authors thank The Ohio State University Comprehensive Cancer Center’s Genomics Shared Resource for technical support. We also thank members of the Summers laboratory for insightful discussion and constructive comments on the manuscript. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funders	Funder number
Ohio State University Comprehensive Cancer Center
Ohio State University Comprehensive Cancer Center/Department
National Institutes of Health
American Cancer Society	RSG-18-066-01-TBG
National Cancer Institute	R03CA227206, P30CA016058
National Institute of General Medical Sciences	R01 GM108743, R01 GM112895
Ohio State University

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title = "Chk1-mediated phosphorylation of Cdh1 promotes the SCFβTRCP-dependent degradation of Cdh1 during S-phase and efficient cell-cycle progression",

abstract = "APC/CCdh1 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/CCdh1 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 SCFβTRCP 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/CCdh1 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/CCdh1 activity that enhances the replication process.",

author = "Debjani Pal and Torres, {Adrian E.} and Stromberg, {Benjamin R.} and Messina, {Abbey L.} and Dickson, {Andrew S.} and Kuntal De and Belinda Willard and Monica Venere and Summers, {Matthew K.}",

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AU - Torres, Adrian E.

AU - Stromberg, Benjamin R.

AU - Messina, Abbey L.

AU - Dickson, Andrew S.

AU - De, Kuntal

AU - Willard, Belinda

AU - Venere, Monica

AU - Summers, Matthew K.

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N2 - APC/CCdh1 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/CCdh1 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 SCFβTRCP 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/CCdh1 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/CCdh1 activity that enhances the replication process.

AB - APC/CCdh1 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/CCdh1 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 SCFβTRCP 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/CCdh1 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/CCdh1 activity that enhances the replication process.

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Chk1-mediated phosphorylation of Cdh1 promotes the SCF^βTRCP-dependent degradation of Cdh1 during S-phase and efficient cell-cycle progression

Abstract

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