The importance of microtubule-dependent tension in accurate chromosome segregation

Abstract

Accurate chromosome segregation is vital for cell and organismal viability. The mitotic spindle, a bipolar macromolecular machine composed largely of dynamic microtubules, is responsible for chromosome segregation during each cell replication cycle. Prior to anaphase, a bipolar metaphase spindle must be formed in which each pair of chromatids is attached to microtubules from opposite spindle poles. In this bipolar configuration pulling forces from the dynamic microtubules can generate tension across the sister kinetochores. The tension status acts as a signal that can destabilize aberrant kinetochore-microtubule attachments and reinforces correct, bipolar connections. Historically it has been challenging to isolate the specific role of tension in mitotic processes due to the interdependency of attachment and tension status at kinetochores. Recent technical and experimental advances have revealed new insights into how tension functions during mitosis. Here we summarize the evidence that tension serves as a biophysical signal that unifies multiple aspects of kinetochore and centromere function to ensure accurate chromosome segregation.

Keywords: chromosome segregation; kinetochore; microtubule; spindle checkpoint; tension.

FIGURE 1

Models of microtubule-associated forces in metaphase and anaphase mitotic spindles. The spindle is composed of three major classes of microtubules (interpolar, kinetochore, and astral), each with unique functions that contribute to the forces generated within the bipolar structure. The forces of note include pushing and pulling forces resulting from microtubule polymerization and depolymerization, respectively, which are largely responsible for chromosome movement (1 and 2), and resistive forces, or tension, generated across pairs of sister kinetochores and centromeres, which are coupled by centromere-associated condensin and cohesin protein complexes (3). MAPs (microtubule associated proteins) crosslink antiparallel interpolar microtubules to create a stable midzone that allows kinesin motor proteins to generate sliding forces that push the spindle poles apart (4). While all four types of forces are active in metaphase spindles, tension across sisters is terminated by cohesion cleavage at the metaphase-to-anaphase transition while anaphase chromosome movement is dominated by microtubule-generated pulling forces.

FIGURE 2

Model of a simplified yeast kinetochore-microtubule attachment with a catch bond-like connection. While many proteins comprise the kinetochore and/or participate in the microtubule-kinetochore attachment, two structures of note are the Ndc80 complex and the Dam1/DASH complex ring. As the end-on microtubule depolymerizes into tubulin heterodimers, the 13 protofilaments each curve outward. These protofilaments are constrained within the collar formed by the ring of Dam1/DASH complexes, and their bending drives the collar further onto the depolymerizing microtubule. The Dam1/DASH ring then pulls the associated centromere/kinetochore via the Ndc80-mediated coupling. This pulling force could potentially be sensed by the Dam1/DASH complex, Ndc80, other outer or inner kinetochore proteins, centromere-associated proteins, DNA, or proteins involved in the coupling between the sister centromeres.

FIGURE 3

Microtubule-generated tension serves as a unifying force that facilitates the processes that promote chromosome segregation during mitosis. Dynamic microtubules generate pushing and pulling forces that move chromosomes as well as alter kinetochore/centromere structure, which may stabilize attachments and silence spindle assembly checkpoint signaling. The tension status at kinetochores also mediates Aurora B-dependent error correction and regulates the timing of anaphase onset.