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

TY - JOUR

T1 - Dynamic kinetochore size regulation promotes microtubule capture and chromosome biorientation in mitosis

AU - Sacristan, Carlos

AU - Ahmad, Misbha Ud Din

AU - Keller, Jenny

AU - Fermie, Job

AU - Groenewold, Vincent

AU - Tromer, Eelco

AU - Fish, Alexander

AU - Melero, Roberto

AU - Carazo, José María

AU - Klumperman, Judith

AU - Musacchio, Andrea

AU - Perrakis, Anastassis

AU - Kops, Geert Jpl

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

U2 - 10.1038/s41556-018-0130-3

DO - 10.1038/s41556-018-0130-3

M3 - Article

C2 - 29915359

SN - 1465-7392

VL - 20

SP - 800

EP - 810

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 7

ER -