Connecting up and clearing out: how kinetochore attachment silences the spindle assembly checkpoint.
With the goal of creating two genetically identical daughter cells, cell division culminates in the equal segregation of sister chromatids. This phase of cell division is monitored by a cell cycle checkpoint known as the spindle assembly checkpoint (SAC). The SAC actively prevents chromosome segregation while one or more chromosomes, or more accurately kinetochores, remain unattached to the mitotic spindle. Such unattached kinetochores recruit SAC proteins to assemble a diffusible anaphase inhibitor. Kinetochores stop production of this inhibitor once microtubules (MTs) of the mitotic spindle are bound, but productive attachment of all kinetochores is required to satisfy the SAC, initiate anaphase, and exit from mitosis. Although mechanisms of kinetochore signaling and SAC inhibitor assembly and function have received the bulk of attention in the past two decades, recent work has focused on the principles of SAC silencing. Here, we review the mechanisms that silence SAC signaling at the kinetochore, and in particular, how attachment to spindle MTs and biorientation on the mitotic spindle may turn off inhibitor generation. Future challenges in this area are highlighted towards the goal of building a comprehensive molecular model of this process.
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. G.J.P.L.Kops@umcutrecht.nl
Geert J P L
GJ
Kops
Jagesh V
JV
Shah
D000818:Animals; D020090:Chromosome Segregation; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D008938:Mitosis; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*