The RepID-CRL4 Ubiquitin Ligase Complex Regulates Metaphase to Anaphase Transition via BUB3 Degradation

Nat Commun. 2020 Jan 7;11(1):24. doi: 10.1038/s41467-019-13808-9.

Abstract

The spindle assembly checkpoint (SAC) prevents premature chromosome segregation by inactivating the anaphase promoting complex/cyclosome (APC/C) until all chromosomes are properly attached to mitotic spindles. Here we identify a role for Cullin-RING ubiquitin ligase complex 4 (CRL4), known for modulating DNA replication, as a crucial mitotic regulator that triggers the termination of the SAC and enables chromosome segregation. CRL4 is recruited to chromatin by the replication origin binding protein RepID/DCAF14/PHIP. During mitosis, CRL4 dissociates from RepID and replaces it with RB Binding Protein 7 (RBBP7), which ubiquitinates the SAC mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by associating with promyelocytic leukemia (PML) nuclear bodies, ensuring its availability upon mitotic onset. Deficiencies in RepID, CRL4 or RBBP7 delay mitotic exit, increase genomic instability and enhance sensitivity to paclitaxel, a microtubule stabilizer and anti-tumor drug.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Anaphase*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Metaphase*
  • Mitosis
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism*
  • Promyelocytic Leukemia Protein / genetics
  • Promyelocytic Leukemia Protein / metabolism
  • Protein Binding
  • Proteolysis
  • Retinoblastoma-Binding Protein 7 / genetics
  • Retinoblastoma-Binding Protein 7 / metabolism
  • Spindle Apparatus / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • BUB3 protein, human
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • PHIP protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Promyelocytic Leukemia Protein
  • Retinoblastoma-Binding Protein 7
  • PML protein, human
  • Ubiquitin-Protein Ligases
  • CRL4 protein, human