Trends in Cell Biology
Volume 23, Issue 9, September 2013, Pages 433-441
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Review
Knowing when to cut and run: mechanisms that control cytokinetic abscission

https://doi.org/10.1016/j.tcb.2013.04.006Get rights and content

Highlights

  • Spatiotemporal coordination of the abscission machinery is required for completion of cytokinesis.

  • CEP55 and MITD1 play key roles in the temporal regulation of the abscission machinery.

  • NoCut prevents DNA damage by delaying abscission in the context of lagging chromosomes.

Abscission, the final step of cytokinesis, mediates the severing of the membrane tether, or midbody, that connects two daughter cells. It is now recognized that abscission is a complex process requiring tight spatiotemporal regulation of its machinery to ensure equal chromosome segregation and cytoplasm content distribution between daughter cells. Failure to coordinate these events results in genetic damage. Here, we review recent evidence suggesting that proper abscission timing is coordinated by cytoskeletal rearrangements and recruitment of regulators of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery such as CEP55 and MIT-domain-containing protein 1 (MITD1) to the abscission site. Additionally, we discuss the surveillance mechanism known as the Aurora B-mediated abscission checkpoint (NoCut), which prevents genetic damage by ensuring proper abscission delay when chromatin is trapped at the midbody.

Section snippets

Cytokinesis and abscission are highly regulated

In animal cells, after nuclear envelope breakdown and chromosome separation during mitosis, cytokinesis leads to the partition of a single cell into two daughter cells. Cytokinesis begins with ingression of the cleavage furrow mediated by contraction of the actomyosin ring. As furrowing progresses, the spindle midzone (see Glossary) transforms into an intercellular bridge or midbody that connects the two dividing cells. The midbody contains antiparallel arrays of microtubules that meet at the

Mechanistic insights into abscission

Although most of the early cytokinetic events that precede furrow ingression and midbody formation have been widely studied, we have only recently started to understand the molecular mechanisms that contribute to the later steps of cytokinesis and abscission (Figure 1).

The midbody serves as a platform to orchestrate the cytoskeleton rearrangements, plasma membrane remodeling, and recruitment of the functional complexes needed for abscission. Before abscission occurs, a secondary ingression site

Membrane dynamics and cytoskeleton changes required for abscission

Local changes of specific phosphoinositides (PtdIns) at the cleavage furrow and midbody membrane are essential to modulate the recruitment and activity of several proteins needed for cytokinesis. Accordingly, phosphatidylinositol-3-monophosphate (PtdIns(3)P)-positive endosomes localize to the midbody during cytokinesis and depletion of the VPS34 or Beclin 1 subunits of the class III phosphatidylinositol-3-OH kinase (PtdIns3K-III), which mediates PtdIns(3)P formation, results in cytokinesis

Controlling abscission timing by ordered recruitment of the abscission machinery

It has become increasingly apparent that the spatiotemporal coordination of the events described above is essential for completion of cytokinesis. Two proteins recently found to be involved in abscission regulation are discussed in this section, namely CEP55 and MITD1. The timely recruitment of CEP55 after furrow ingression is essential to ensure the correct midbody architecture [45]. Subsequently, MITD1 may serve two purposes in the events leading to abscission 46, 47, by increasing midbody

Regulation of abscission timing by the NoCut pathway

Before cytokinesis starts, chromosomes need to be fully cleared from the cleavage plane to avoid being damaged during furrow formation [55]. Similarly, abscission must occur only after the complete separation of sister chromatids, because erroneous chromosome segregation can lead to aberrant cytokinesis resulting in the formation of tetraploid cells and cancer 56, 57. Therefore, to protect cells against genomic instability and its deleterious effects, a surveillance mechanism or checkpoint is

An intriguing connection between nuclear pores and abscission control

An alternative way of activating an Aurora B-dependent abscission delay that involves the nuclear pore has been found in human cells. Following mitotic DNA segregation and cytokinesis initiation, the chromosomes are decondensed and the nuclear envelope is reformed. The nucleoporins (Nup) ELYS/MEL-28, Nup153, and Nup50 are rapidly recruited to the decondensing chromatin and aid in the recruitment of membranes to form the nuclear envelope and other Nup subunits, which rapidly assemble into

Concluding remarks

The last few years have seen rapid and exciting advances in our understanding of the various molecular mechanisms regulating cytokinetic abscission. Despite the original idea of cells separating by simply rupturing their midbodies, it is now clear that abscission is a complex and extremely regulated process that requires a myriad of cellular functions, including vesicle trafficking, cytoskeletal rearrangements, and a machinery that mediates membrane scission. Live-cell imaging by time-lapse

Acknowledgments

The authors thank Anna Caballe, Leticia Labrador, and Stuart Neil for critical comments on the manuscript. J.M-S. is funded by the Medical Research Council (G0802777), the Lister Institute for Preventative Medicine, and the EMBO Young Investigator Program. J.M-S. and M.A. are funded by a Wellcome Trust grant (WT093056MA).

Glossary

Apoptosis-linked gene-2-interacting protein X (ALIX)
cytoplasmic protein first characterized as a binding partner of ALG-2. ALIX is also an ESCRT-associated protein that functions in cytokinesis by recruiting ESCRT-III to the midbody.
Central spindle
region at the center of the spindle midzone that originates the intercellular bridge or midbody. Among other proteins, central spindle assembly requires the central spindlin complex, which comprises the kinesin-like protein MKLP1 and the Rho family

References (79)

  • S.H. Low

    Syntaxin 2 and endobrevin are required for the terminal step of cytokinesis in mammalian cells

    Dev. Cell

    (2003)
  • J.K. Schweitzer et al.

    Finishing the job: cytoskeletal and membrane events bring cytokinesis to an end

    Exp. Cell Res.

    (2004)
  • S.J. Field

    PtdIns(4,5)P2 functions at the cleavage furrow during cytokinesis

    Curr. Biol.

    (2005)
  • A. Echard

    Terminal cytokinesis events uncovered after an RNAi screen

    Curr. Biol.

    (2004)
  • G.T. Charras

    Life and times of a cellular bleb

    Biophys. J.

    (2008)
  • C. Norden

    The NoCut pathway links completion of cytokinesis to spindle midzone function to prevent chromosome breakage

    Cell

    (2006)
  • P. Steigemann

    Aurora B-mediated abscission checkpoint protects against tetraploidization

    Cell

    (2009)
  • M.S. van der Waal

    Cell division control by the Chromosomal Passenger Complex

    Exp. Cell Res.

    (2012)
  • K. Hofmann

    Ubiquitin-binding domains and their role in the DNA damage response

    DNA Repair (Amst.)

    (2009)
  • R. Bermejo

    Preserving the genome by regulating chromatin association with the nuclear envelope

    Trends Cell Biol.

    (2012)
  • J.M. Mullins et al.

    Terminal phase of cytokinesis in D-98s cells

    J. Cell Biol.

    (1977)
  • U.S. Eggert

    Animal cytokinesis: from parts list to mechanisms

    Annu. Rev. Biochem.

    (2006)
  • J.P. Fededa et al.

    Molecular control of animal cell cytokinesis

    Nat. Cell Biol.

    (2012)
  • A. Caballe et al.

    ESCRT machinery and cytokinesis: the road to daughter cell separation

    Traffic

    (2011)
  • N. Elia

    Dynamics of endosomal sorting complex required for transport (ESCRT) machinery during cytokinesis and its role in abscission

    Proc. Natl. Acad. Sci. U.S.A.

    (2011)
  • J. Guizetti

    Cortical constriction during abscission involves helices of ESCRT-III-dependent filaments

    Science

    (2011)
  • J.H. Hurley et al.

    Membrane budding and scission by the ESCRT machinery: it's all in the neck

    Nat. Rev. Mol. Cell Biol.

    (2010)
  • B. McDonald et al.

    No strings attached: the ESCRT machinery in viral budding and cytokinesis

    J. Cell Sci.

    (2009)
  • J. McCullough

    Membrane fission reactions of the mammalian ESCRT pathway

    Annu. Rev. Biochem.

    (2013)
  • J.G. Carlton et al.

    Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery

    Science

    (2007)
  • E. Morita

    Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis

    EMBO J.

    (2007)
  • H.H. Lee

    Midbody targeting of the ESCRT machinery by a noncanonical coiled coil in CEP55

    Science

    (2008)
  • J.G. Carlton

    Differential requirements for Alix and ESCRT-III in cytokinesis and HIV-1 release

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • S. Lekomtsev

    Evidence that the tumor-suppressor protein BRCA2 does not regulate cytokinesis in human cells

    J. Cell Sci.

    (2010)
  • P.I. Hanson

    Plasma membrane deformation by circular arrays of ESCRT-III protein filaments

    J. Cell Biol.

    (2008)
  • G. Effantin

    ESCRT-III CHMP2A and CHMP3 form variable helical polymers in vitro and act synergistically during HIV-1 budding

    Cell. Microbiol.

    (2013)
  • M. Agromayor

    Essential role of hIST1 in cytokinesis

    Mol. Biol. Cell

    (2009)
  • M. Bajorek

    Biochemical analyses of human IST1 and its function in cytokinesis

    Mol. Biol. Cell

    (2009)
  • M. Bajorek

    Structural basis for ESCRT-III protein autoinhibition

    Nat. Struct. Mol. Biol.

    (2009)
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