Cyclin-dependent Kinase 1 (CDK1)-dependent Inhibition of the E3 Ubiquitin Ligase, CRL4CDT2, Ensures Robust Transition from S Phase to Mitosis [Protein Synthesis and Degradation]

November 19th, 2014 by Rizzardi, L. F., Coleman, K. E., Varma, D., Matson, J. P., Oh, S., Cook, J. G.

Replication-coupled destruction of a cohort of cell cycle proteins ensures efficient and precise genome duplication. Three proteins destroyed during replication via the CRL4CDT2 ubiquitin E3 ligase, CDT1, p21, and SET8 (PR-SET7), are also essential or important during mitosis making their re-accumulation after S phase a critical cell cycle event. During early and mid-S phase and during DNA repair, PCNA loading onto DNA (PCNADNA) triggers the interaction between CRL4CDT2 and its substrates resulting in their degradation. We have discovered that beginning in late S phase, PCNADNA is no longer sufficient to trigger CRL4CDT2-mediated degradation. A CDK1-dependent mechanism that blocks CRL4CDT2 recruitment to chromatin actively protects CRL4CDT2 substrates. We postulate that deliberate override of replication-coupled destruction allows anticipatory accumulation in late S phase. We further show that (as for CDT1) de novo SET8 re-accumulation is important for normal mitotic progression. In this manner, CDK1-dependent CRL4CDT2 inactivation contributes to efficient transition from S phase to mitosis.
  • Posted in Journal of Biological Chemistry, Publications
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