Centromere tension: a divisive issue

Abstract

It has been proposed that the spindle assembly checkpoint detects both unattached kinetochores and lack of tension between sister kinetochores when sister chromatids are not attached to opposite spindle poles. However, here we argue that there is only one signal — whether kinetochores are attached to microtubules or not — and this has implications for our understanding of both chromosome segregation and the control of genomic stability.

Figure 1

Classic experiments that revealed the link between tension, stability of attachment and control of mitotic progression. (a) Kinetochore attachment and chromosome orientation in mitosis. Types of kinetochore attachment are indicated. Types of chromosome orientation: M, mono-oriented; B, bi-oriented. There is no strict coordination between the type of kinetochore attachment and chromosome orientation. Bi-oriented chromosomes can be attached in a proper (amphitelic) or erroneous (merotelic) fashion. Similarly, chromosome mono-orientation can be caused by a transient monotelic state, which is a normal intermediate before proper amphitelic attachment, or erroneous syntelic attachment. For error-free chromosome distribution, incorrect microtubule connections (shown in red) must be resolved, whereas proper microtubule connections (shown in green) should be preserved. (b) During mitosis in vertebrate somatic cells, monotelic chromosomes delay anaphase. Laser ablation of the unattached kinetochore allows mitotic progression to resume although the chromosome remains mono-oriented and centromere tension remains low. (c) During meiosis I in spermatocytes of praying mantids, a mono-oriented unpaired X chromosome delays anaphase. Sister kinetochores are fused and are a single functional unit during meiosis I. Thus, unpaired X chromosomes during meiosis I could be analogous to monotelic chromosomes that lack unattached kinetochores during mitosis. However, the effects of these chromosomes on mitotic versus meiotic progression are markedly different. Pull the unpaired X chromosome away with a microneedle relieves the block and allows the cell to initiate anaphase. (d) Using a microneedle to pulling on a syntelic chromosome at the spindle pole leads to a marked increase in the number of microtubules in the kinetochore fibres (red lines) during meiosis I in grasshopper spermatocytes.

Figure 2

Potential mechanisms of intrakinetochore deformations. (a) A kymograph depicting the dynamics of sister kinetochores in HeLa cells (reproduced with permission from ref. 31). Inset presents time points 9–18 s, at higher magnification. Kinetochores are double-labelled with an inner-kinetochore component CENP-A–GFP (green fluorescent protein; green) and an outer kinetochore component Mis12–mCherry (red). Notice that the red and green labels are periodically superimposed and separated, which reflects intrakinetochore deformations. Intriguingly, deformation of sister kinetochores are not coordinated. Also, intrakinetochore deformations occur several times during a single chromosome oscillation cycle and they are therefore not coordinated with the direction of the chromosome movement. (b) Predicted dynamics of the centromere/kinetochores if they are modelled as a tandem of Hookean springs. In the absence of attached microtubules both intrakinetochore- (red) and interkinetochore- (green) elastic elements are relaxed (top). Depending on the relative stiffness of the centromere and kinetochores, microtubule-based forces (black arrows) can primarily stretch the centromere (if the kinetochores are stiffer springs; middle) or the kinetochores (if the centromere is stiffer; bottom). However, in both models, it is impossible to stretch one kinetochore while its identical sister is relaxed. (c) A potential mechanism of intrakinetochore deformation. Our speculation is based on electron-microscopy reconstructions that reveal a fibrous connection between the kinetochore and microtubule walls approximately 50–100 nm away from the microtubule tip. In amphitelic configuration, poleward forces acting along microtubules (black arrows) are responsible for stretching the centromere (green spring). Intrakinetochore stretching occurs when growing tips of kinetochore microtubules push against the kinetochore inner layer which stretches the fibrous connection (red spring in the left kinetochore). When microtubules are shrinking or not dynamic, the fibrous connection collapses (red spring in the right kinetochore). In this model, the deformation of sister kinetochores is not coordinated.