Mitosis: Chromosome Segregation and Stability

Abstract

Mammalian cells are charged with the task of evenly distributing 46 chromosomes to each of two daughter cells during every mitotic cell division. This is achieved by a microtubule‐based cellular structure termed the mitotic spindle. However, numerous cellular and/or genetic defects are known to impair the fidelity of mitosis and promote chromosome segregation errors and aneuploidy. Missegregation of even a single chromosome leads to the deregulated expression of hundreds to thousands of genes, including many that are involved in essential processes such as DNA replication, repair and mitosis. Consequently, while aneuploidy is most typically detrimental to cell viability, it also has the potential to initiate a self‐propagating cycle of chromosome instability that can ultimately promote tumour initiation, progression and relapse.

Key Concepts

  • Chromosome segregation is driven by the mitotic spindle.
  • Multiple genetic and/or cell biological defects are known to cause chromosome missegregation and aneuploidy.
  • Aneuploidy is poorly tolerated in normal cells.
  • Cancer cells adapt to tolerate aneuploidy.
  • Cells that persistently missegregate chromosomes are termed chromosomally unstable (CIN).
  • CIN promotes tumour initiation, progression and relapse and correlates with poor patient prognosis.
  • Aneuploidy and CIN are hallmarks of human tumours.

Keywords: centrosome; micronucleus; merotelic; cohesion; spindle assembly checkpoint; tetraploidy; lagging chromosome

Figure 1. The centrosome duplication cycle. Centrosome duplication begins in G1 phase, when the disengaged centrioles (purple cylinders) separate and begin to replicate new daughter centrioles. This process continues through S‐phase and is finished by late G2. At this phase of the cell cycle, the two pairs of centrioles each make up their own centrosomal complex. Upon mitotic entry, the two centrosomes separate and nucleate microtubules (orange lines) important for bipolar spindle assembly. Late in mitosis, the two centrioles in each centrosome disengage, thereby licensing them for a second round of duplication in the following G1.
Figure 2. Cancer cells exhibit spindle assembly defects and abnormal chromosome segregation. During normal mitosis (a), two centrosomes (green) nucleate the microtubules (red) that are important for bipolar spindle assembly and normal chromosome alignment (chromosome, white). By contrast, many cancer cells possess extra centrosomes and/or display abnormal spindle assembly (b). These defects promote the formation of merotelic attachments and can induce highly abnormal chromosome segregation during anaphase (c). Images from Lim and Ganem (Oncotarget, ) reproduced under the Creative Commons Attribution‐Share Alike 3.0 Unported license. http://creativecommons.org/licenses/by/3.0/.
Figure 3. Mechanisms underlying chromosome missegregation. It is now established that multiple mechanisms can lead to chromosome missegregation in human cells. These include defects in the spindle assembly checkpoint (a), which enables anaphase onset before all chromosomes achieving stable bi‐oriented attachments to the mitotic spindle; cohesion defects (b), which disrupt the normal back‐to‐back geometry of sister chromatids that normally promotes bi‐orientation and the formation of merotelic attachments (c), in which single kinetochores bind to microtubules emanating from opposite spindle poles. (d) Extra centrosomes, which are common in cancer cells, promote the formation of merotelic attachments by enabling cells to pass through a transient multipolar intermediate, during which time merotelic attachments accumulate. Many of these merotelic attachments persist even after centrosome clustering and bipolar spindle assembly in cancer cells, likely owing in large part to inefficient correction of merotelics due to hyper‐stable kinetochore microtubules.
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Mustaly, Hatim M, and Ganem, Neil J(Mar 2015) Mitosis: Chromosome Segregation and Stability. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005774.pub2]