Genome stability is ensured by temporal control of kinetochore–microtubule dynamics

Abstract

SummaryMost solid tumors are aneuploid and many frequently mis-segregate chromosomes. This chromosomal instability is commonly caused by persistent maloriented attachment of chromosomes to spindle microtubules. Chromosome segregation requires stable microtubule attachment at kinetochores, yet those attachments must be sufficiently dynamic to permit correction of malorientations. How this balance is achieved is unknown, and the permissible boundaries of attachment stability versus dynamics essential for genome stability remain poorly understood. Here we show that two microtubule-depolymerizing kinesins, Kif2b and MCAK, stimulate kinetochore-microtubule dynamics during distinct phases of mitosis to correct malorientations. Few-fold reductions in kinetochore-microtubule turnover, particularly in early mitosis, induce severe chromosome segregation defects. In addition, we show that stimulation of microtubule dynamics at kinetochores restores chromosome stability to chromosomally unstable tumor cell lines, establishing a causal relationship between deregulation of kinetochore-microtubule dynamics and chromosomal instability. Thus, temporal control of microtubule attachment to chromosomes during mitosis is central to genome stability in human cells.

Prime movers: the mechanochemistry of mitotic kinesins

“…Indeed, full length and truncated KIF10 dimers can track growing microtubule tips for several seconds 128,129 and full length KIF10 can track shrinking tips, requiring both motor activity and a C-terminal nonmotor microtubule binding site to do so 128 . There are also data suggesting that KIF10 may influence the dynamics of kinetochore-attached microtubules: a truncated human KIF10 construct accelerates microtubule growth in the presence of low concentrations of taxol 130 .…”

“…Dimerisation increases catastrophase activity but is not required for it 125,176 ; as KIF2 monomers are effective. The proximal part of the N-terminal neck is positively charged and this accelerates the initial recruitment of the motor to the microtubule 54,176 .…”

Dynein prevents erroneous kinetochore-microtubule attachments in mitosis

“…Syntelic attachments occur when both sister kinetochores become attached by microtubules originated from a single pole, while merotelic attachments arise when a single kinetochore becomes attached to both spindle poles. The beststudied error correction system is based on the action of the centromere-localized kinase Aurora B, which destabilizes kinetochore-microtubule attachments through phosphorylation of microtubule depolymerases (such as the kinesin-13 proteins MCAK and Kif2B) [33][34][35] and Ndc80, a protein required for the stabilization of end-on kinetochore-microtubule attachments. [36][37][38] Once chromosomes become bi-oriented and tension is applied between sister kinetochores, Ndc80 moves away from Aurora B, resulting in kinetochoremicrotubule attachment stabilization.…”

Drosophila S2 Cells as a Model System to Investigate Mitotic Spindle Dynamics, Architecture, and Function

“…This requires a labile interface that enables microtubules to slip and eventually detach from the kinetochore in response to a poleward force, whose origin remains controversial (Cameron et al, 2006;Dumont and Mitchison, 2009;Ganem et al, 2005;Matos et al, 2009;Miyamoto et al, 2004;Rogers et al, 2004). The importance of a labile kinetochore-microtubule interface is reflected in the capacity to correct mistakes inherent to the stochastic nature of mitotic spindle assembly and the interaction between microtubules and chromosomes (Bakhoum et al, 2009b;Ganem et al, 2005;Matos et al, 2009). In fact, increasing the stability of kinetochore-microtubule attachments in a way that errors could more difficultly be corrected is, by itself, sufficient to induce chromosomal instability in once stable diploid cells (Bakhoum et al, 2009a).…”