Key Points
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A signalling network known as the mitotic exit network (MEN) in S. cerevisiae and the septation initiation network (SIN) in S. pombe, although conserved, seem to regulate different cell-cycle transitions in the two yeasts. MEN regulates the inactivation of mitotic CDKs at the end of mitosis, whereas SIN controls cytokinesis after mitotic CDK inactivation.
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But, although these two pathways seem different at first glance, studies are beginning to indicate that the pathways, their regulation and their outputs might not actually be that different. Based on this, we propose that MEN and SIN have similar functions in budding and fission yeast - that is, to both downregulate mitotic CDKs and promote cytokinesis.
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Therefore, to understand how the cell ensures that the exit from mitosis and cytokinesis occur only at the end of each cell cycle, it will crucial to identify all the signals that control and regulate the MEN and SIN.
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There is also evidence for homologues of these pathways in higher eukaryotes. Further work might not only shed light on how exit from mitosis and cytokinesis are regulated in higher eukaryotes but also explain some of the mechanisms that lead to aneuploidy, which is often associated with cancerous transformation.
Abstract
A conserved signalling cascade — termed the mitotic-exit network in budding yeast and the septation-initiation network in fission yeast — controls key events during exit from mitosis and cytokinesis. Although the components of these signalling networks are highly conserved between the two yeasts, the outputs seem quite different. How, then, do these two pathways function, and how are they regulated?
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Acknowledgements
We are grateful to D. McCollum and V. Simanis for communicating results before publication. We thank members of the Amon lab for comments on the manuscript and apologize to our colleagues whose work we could not include due to space limitations.
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Glossary
- MITOTIC SPINDLE
-
An array of microtubules that forms during mitosis to which chromosomes attach and by which chromosomes are segregated to separate daughter cells.
- CENTROSOME
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The higher eukaryotic equivalent of the spindle-pole body, the centrosome nucleates microtubules, including those that will form the mitotic spindle. It contains two barrel-shaped structures known as centrioles.
- CHROMOSOME DECONDENSATION
-
On entry into mitosis, chromosomes become compacted or 'condensed'. This is especially apparent in fission yeast and higher eukaryotes. During exit from mitosis, this process is reversed and chromosomes become less compacted — a process known as decondensation.
- SPINDLE ELONGATION (ANAPHASE B)
-
After the chromosomes have been pulled to centrosomes, the mitotic spindle lengthens (and in budding yeast, pushes into the growing daughter cell), thereby allowing further separation of the chromosomes.
- UBIQUITIN LIGASE
-
An enzyme which, together with a ubiquitin-conjugating enzyme, attaches ubiquitin peptides to a substrate protein.
- 26S PROTEASOME
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A multi-subunit protease that degrades poly-ubiquitylated proteins.
- COHESIN
-
A protein complex that tethers sister chromatids together from the time they are created (during DNA replication) until cohesin cleavage at the onset of anaphase.
- GTPASE-ACTIVATING PROTEIN (GAP)
-
A protein that inhibits GTPases by increasing their intrinsic ability to hydrolyse GTP, which allows for shorter time in the active, GTP-bound state.
- GUANINE-NUCLEOTIDE EXCHANGE FACTOR (GEF)
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A protein that activates GTPases by facilitating the exchange of GDP for GTP, thereby allowing for shorter time in the inactive, GDP-bound state.
- POLO KINASE
-
A family of related kinases defined by a conserved region known as the polo box. They are thought to have several roles in the cell, including an important role in centrosome duplication.
- SECURIN
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(Pds1 in budding yeast, cut2 in fission yeast.) Securin is responsible for keeping separase inactive until metaphase, at which point securin is degraded, thereby liberating separase which, in turn, cleaves the cohesins.
- SEPARASE
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(Esp1 in budding yeast, cut1 in fission yeast.) A protease that cleaves the cohesin subunit Scc1/Mcd1/Rad21 at two specific sites. Cleavage of these sites by separase allows sister chromatids to separate, leading to the onset of anaphase.
- SISTER CHROMATIDS
-
Chromosomes that have been duplicated during S phase. Sister chromatids are held together by cohesins until metaphase.
- KINETOCHORE
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A proteinaceous structure that mediates attachment of the chromosomes to microtubules.
- MEDIAL RING
-
A structure in fission yeast, containing F-actin and numerous other proteins, which marks the eventual site of the division septum.
- 1,3-β-GLUCAN SYNTHASE
-
An enzyme that makes 1,3-β-glucan, a sugar polymer that is a structural component of the division septum in fission yeast.
- F-ACTIN
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Filamentous actin. Contraction of filamentous actin is thought to have an important role in cytokinesis.
- RAB FAMILY
-
A conserved family of GTPases whose members are involved in endocytic and exocytic vesicle transport.
- MIDBODY
-
A region of dense matrix material visible in higher eukaryotic cells by electron microscopy. The midbody remains between two daughter cells after the cleavage furrow has contracted.
- CLEAVAGE FURROW
-
A region of the cell membrane in higher eukaryotic cells that ingresses; thought to be a result of contraction of actin and myosin rings.
- CENTRIOLE
-
A cylindrical array of microtubules, two of which are found in the centre of centrosomes and are responsible for nucleation of microtubules.
- ACTOMYOSIN AND SEPTIN DYNAMICS
-
Actomyosin and septin dynamics refers to the contraction of actin, myosin, and septin rings, which is concurrent with cytokinesis in eukaryotic cells.
- ANEUPLOIDY
-
An abnormal number of chromosomes caused by their inaccurate segregation during cell division.
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Bardin, A., Amon, A. MEN and SIN: what's the difference?. Nat Rev Mol Cell Biol 2, 815–826 (2001). https://doi.org/10.1038/35099020
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DOI: https://doi.org/10.1038/35099020
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