Dynamic kinetochore size regulation promotes microtubule capture and chromosome biorientation in mitosis

Nat Cell Biol. 2018 Jul;20(7):800-810. doi: 10.1038/s41556-018-0130-3. Epub 2018 Jun 18.

Abstract

Faithful chromosome segregation depends on the ability of sister kinetochores to attach to spindle microtubules. The outer layer of kinetochores transiently expands in early mitosis to form a fibrous corona, and compacts following microtubule capture. Here we show that the dynein adaptor Spindly and the RZZ (ROD-Zwilch-ZW10) complex drive kinetochore expansion in a dynein-independent manner. C-terminal farnesylation and MPS1 kinase activity cause conformational changes of Spindly that promote oligomerization of RZZ-Spindly complexes into a filamentous meshwork in cells and in vitro. Concurrent with kinetochore expansion, Spindly potentiates kinetochore compaction by recruiting dynein via three conserved short linear motifs. Expanded kinetochores unable to compact engage in extensive, long-lived lateral microtubule interactions that persist to metaphase, and result in merotelic attachments and chromosome segregation errors in anaphase. Thus, dynamic kinetochore size regulation in mitosis is coordinated by a single, Spindly-based mechanism that promotes initial microtubule capture and subsequent correct maturation of attachments.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation*
  • Dyneins / genetics
  • Dyneins / metabolism
  • Female
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism
  • Kinetochores / pathology*
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / genetics
  • Microtubules / metabolism
  • Microtubules / pathology*
  • Mitosis*
  • Protein Binding
  • Signal Transduction
  • Spindle Apparatus / genetics
  • Spindle Apparatus / metabolism
  • Spindle Apparatus / pathology*
  • Time Factors
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology*

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • KNTC1 protein, human
  • Microtubule-Associated Proteins
  • SPDL1 protein, human
  • ZW10 protein, human
  • Zwilch protein, human
  • Dyneins