Mitosis and Meiosis: Molecular Control of Chromosome Separation


Accurate chromosome segregation during both mitosis and meiosis is governed by an intricate and synchronised cascade of events. These are controlled by the molecular networks that ensure the proper assembly of sister deoxyribonucleic acid (DNA) molecules produced during DNA replication, followed by the action of the spindle that pulls the sister chromatids apart. Mistakes in these processes would lead to chromosome transmission defects and subsequent aneuploidy, a common hallmark of many tumour cells. Herein, we review recent progresses in the molecular illustration of the chromosome architecture and function specially those depending on the structural maintenance of chromosome family of protein complexes, in conjunction with the spatio‐temporal regulation of cell‐cycle progression.

Key Concepts:

  • Cohesin is the glue that entraps duplicated sister DNA.

  • DNA replication is coupled to the establishment of sister‐chromatid cohesion through cohesin acetylation.

  • The bulk of cohesin is removed from chromosome arms by phosphorylation in early stages of mitosis, whereas centromeric cohesin is removed by separase‐mediated cleavage at the metaphase anaphase transition.

  • Condensin is required for a proper mitotic chromosome assembly.

  • Smc family of protein complex determine chromosomal structure and function throughout the cell cycle.

  • Separase is tightly regulated in cell cycle and become active exclusively at the onset anaphase.

  • SAC monitors the presence of unattached kinetochores.

  • Protein degradation mediated by the APC/C drives anaphase onset.

  • Back‐to‐back orientation of kinetochores is required for Meiosis II and mitosis, whereas, side‐by‐side orientation of kinetochores is required for meiosis I.

  • Shugoshin protects precocious dissociation of cehesin.

  • Bi‐orientation of chromosomes depends on the correction mechanisms and spindle assembly checkpoint.

Keywords: chromosome condensation; sister‐chromatid cohesion; cohesin; condensin; Smc; separase; spindle‐assembly checkpoint; anaphase‐promoting complex/cyclosome

Figure 1.

Smc‐protein complexes in eukaryotes. The Smc1–Smc3 heterodimer is the core of the cohesin complex, which also contains Scc1/Rad21 and Scc3/SA subunits. The Smc2‐4 heterodimer appears at the core of the condensin complex, containing also CAP‐H/H2, CAP‐D2/D3 and CAPG/G2 non‐Smc subunits. The Smc5‐6 heterodimer form a less characterised complex, along with six non‐Smc subunits collectively called Nse proteins. Smc, structural maintenance of chromosome.

Figure 2.

Establishment of sister‐chromatid cohesion during DNA synthesis. The activity of Wapl to destabilise cohesin is counteracted by Eco1 (Esco1 and Esco2 in mammals). One possible model would be that the activity of Eco1 associates with the replication fork and thus Eco1 can acetylate the cohesin subunit Smc3 as the replisome pass through the cohesin ring. This acetylation serves as a ‘lock’ function that confers stable association of cohesin to sister chromatids, thereby establishes sister‐chromatid cohesion. Smc, structural maintenance of chromosome.

Figure 3.

Regulation of cohesin dissociation in different organisms. (a) How sister‐chromatid separation is controlled in budding yeast. Cohesin remains associated with chromosomes until metaphase. At the metaphase‐to‐anaphase transition, the Scc1p subunit of cohesin is cleaved by separase, resulting in the cohesin dissociation. (b) In vertebrates, the bulk of cohesin dissociates from chromosomes during prophase in a Polo‐like kinase‐dependent manner. A small amount of cohesin remains associated with metaphase chromosomes, predominantly at centromeres. At the metaphase‐to‐anaphase transition, the remaining fraction of chromatin‐associated cohesin is cleaved by separase, which is removes cohesin completely from chromosomes. APC/C, anaphase‐promoting complex/cyclosome.

Figure 4.

Regulation of sister‐chromatid separation in mitosis. Inhibition of APC/CCdc20 by the spindle assembly checkpoint. Unattached kinetochores are sensed by the spindle assembly checkpoint (SAC). An as yet poorly understood signalling cascade is initiated and results in inhibition of APC/CCdc20. Separase remains inactive and sister‐chromatid separation is inhibited. Once all chromosomes are properly aligned, active APC/CCdc20 ubiquitinates the separase inhibitor securin, as well as Cdk1‐bound cyclin B thereby targeting them for destruction by the 26S proteasome. Cdk1 remains then inactive, whereas active separase is now able to cleave cohesin complexes, thereby initiating the metaphase‐to‐anaphase transition. APC/C, anaphase‐promoting complex/cyclosome; Cdk1, cyclin‐dependent kinase 1.

Figure 5.

Arm and centromeric cohesion are differentially regulated during meiosis. Following recombination events during meiotic prophase, homologous chromosomes are connected by sister‐chromatid cohesion, forming a ‘bivalent’ structure. This cohesion depends on meiosis‐specific cohesin complexes. Both kinetochores of each homolog face in the same direction during meiosis I. (a) At anaphase I, arm cohesion is lost, resulting in the separation of homologous chromosomes. Passage through meiosis I is required for the separation of kinetochores and they face in opposite directions during meiosis II. (b) Resolution of centromeric cohesion allows the separation of sister chromatids at anaphase II.



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Further Reading

Peters JM, Tedeschi A and Schmitz J (2008) The cohesin complexes and its roles in chromosome biology. Genes and Development 22: 3089–3114.

Santaguida S and Musacchio A (2009) The life and miracles of kinetochores. European Molecular Biology Organization Journal 28: 2511–2531.

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Nagasaka, Kota, Gallego‐Paez, Lina M, and Hirota, Toru(Jul 2011) Mitosis and Meiosis: Molecular Control of Chromosome Separation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005917.pub2]