Connecting up and clearing out: how kinetochore attachment silences the spindle assembly checkpoint

Abstract

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.

Thyroid Hormone Receptor Interacting Protein 13 (TRIP13) AAA-ATPase Is a Novel Mitotic Checkpoint-silencing Protein

“…The termination may happen through dynein-mediated stripping of the MAD1⅐C-MAD2 catalyst from kinetochores (47). Proteins, such as protein phosphatase 1 and Spindly, may facilitate the stripping by altering protein modification or composition at kinetochores to concurrently weaken the MAD1⅐C-MAD2 complex associating with its uncharacterized kinetochore receptor and enhance its interaction with the dynein⅐ dynactin complex (48,49). Although p31 comet and TRIP13 are localized at prometaphase kinetochores, it is still unclear how significant a role they play in terminating the "wait anaphase" signal (30,31,50) (Fig.…”

Conditional targeting of MAD1 to kinetochores is sufficient to reactivate the spindle assembly checkpoint in metaphase

“…The SAC monitors the state of attachment of chromosomes to microtubules of the mitotic spindle and halts the cell cycle until all chromosomes have achieved stable biorientation. Unattached kinetochores and/or kinetochores of non-bioriented chromosomes recruit a subset of SAC components that contribute to the generation of a wait-anaphase signal (Musacchio and Salmon 2007; Kops and Shah 2012). Central to this is the MAD1-MAD2 complex that is stably associated with unattached kinetochores (Mapelli and Musacchio 2007).…”

“…Stable attachment of kinetochores to microtubules causes removal of SAC proteins, thereby negating their ability to generate MCC (Kops and Shah 2012). It was recently shown by Maldonado and Kapoor that removal of MAD1 is a key step in shutting down SAC signaling at kinetochores.…”

The KMN protein network – chief conductors of the kinetochore orchestra

“…These include MT-associated proteins in the proximity of kinetochore MT (kMT) plus-ends and members of the spindle assembly checkpoint (SAC) (Fig. 1B) (Musacchio and Salmon, 2007;Kops and Shah, 2012). The KMN network is also thought to associate with proteins that form the peripheral region of the outer kinetochore, including fibrous proteins, such as CENP-F, and MT motor proteins, such as the kinesin CENP-E and the cytoplasmic dynein-dynactin complex (Fig.…”