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

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 SCF?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/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.
Mesh Terms:
Cdh1 Proteins, Cell Cycle Proteins, Checkpoint Kinase 1, HeLa Cells, Humans, Phosphorylation, S Phase, Transfection, Ubiquitin
Cell Death Dis
Date: Dec. 28, 2019
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