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

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

Cell death & disease (2020-04-30)
Debjani Pal, Adrian E Torres, Benjamin R Stromberg, Abbey L Messina, Andrew S Dickson, Kuntal De, Belinda Willard, Monica Venere, Matthew K Summers
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Cdh1 (Ab-2) Mouse mAb (DH01), liquid, clone DH01, Calbiochem®
Sigma-Aldrich
MISSION® esiRNA, targeting human USP37