Cyclin B1-Cdk1 facilitates MAD1 release from the nuclear pore to ensure a robust spindle checkpoint

J Cell Biol. 2020 Jun 1;219(6):e201907082. doi: 10.1083/jcb.201907082.

Abstract

How the cell rapidly and completely reorganizes its architecture when it divides is a problem that has fascinated researchers for almost 150 yr. We now know that the core regulatory machinery is highly conserved in eukaryotes, but how these multiple protein kinases, protein phosphatases, and ubiquitin ligases are coordinated in space and time to remodel the cell in a matter of minutes remains a major question. Cyclin B1-Cdk is the primary kinase that drives mitotic remodeling; here we show that it is targeted to the nuclear pore complex (NPC) by binding an acidic face of the kinetochore checkpoint protein, MAD1, where it coordinates NPC disassembly with kinetochore assembly. Localized cyclin B1-Cdk1 is needed for the proper release of MAD1 from the embrace of TPR at the nuclear pore so that it can be recruited to kinetochores before nuclear envelope breakdown to maintain genomic stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / metabolism*
  • CRISPR-Cas Systems
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism*
  • Exons
  • Gene Editing
  • Genomic Instability / genetics
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism*
  • Mad2 Proteins / genetics
  • Mad2 Proteins / metabolism
  • Mass Spectrometry
  • Mutation
  • Nuclear Envelope / metabolism
  • Nuclear Pore / metabolism*
  • Nuclear Pore Complex Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / genetics*
  • Signal Transduction / physiology
  • Spindle Apparatus / metabolism

Substances

  • Cell Cycle Proteins
  • Cyclin B1
  • MAD1L1 protein, human
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Nuclear Pore Complex Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • TPR protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • TTK protein, human