Editorial: Mechanics and regulation of mitotic exit and cytokinesis

The process of cell division has fascinated scienLsts for generaLons because of its intrinsic beauty and its role in growth, development, and reproducLon in all organisms. Cell division controls the faithful segregaLon of genomic and cytoplasmic materials between two daughter cells and errors during this process have been linked to various human diseases, including cancer (Dominguez-Brauer et al., 2015;Lens and Medema, 2019). This collecLon of arLcles in FronLers of Cell and Developmental Biology focuses on the recent progresses in our understanding of the mechanisms and signalling pathways that regulate exit from mitosis and the separaLon of the two daughter cells during cytokinesis (D'Avino et al., 2015).Once the early mitoLc events are completed and the spindle assembly checkpoint that monitors proper chromosome-spindle a`achments is saLsfied, then cells exit mitosis. This process is unidirecLonal and leads to both the separaLon of the genomic material but also to the re-establishment of all the cellular compartments that have been dismantled or reorganised to allow mitosis to occur. As this process is very rapid and cell synchronisaLon difficult to obtain at this specific stage, research on the early stages of mitoLc exit has lagged behind. However, recent advances started to shed light on key molecular events that regulate this cell cycle transiLon (Vagnarelli, 2021). A breakthrough has been the idenLficaLon of the major protein phosphatases that conduct the reversal of the mitoLc wave of phosphorylaLon; as it has emerged, while kinases govern the early mitosis kingdom, phosphatases reign in the mitoLc exit one. Here two reviews cover the recent advances, from a molecular point of view, on how the birth of a new interphase nucleus is controlled. In the first review, Lacroix, Lorca and Castro (Lacroix et al., 2022) focus on the spaLal and temporal regulaLon of Protein Phosphatase 2A (PP2A), how the recogniLon and specificity for substrates is achieved and how PP2A-B55-dependent dephosphorylaLon drives mitoLc exit. While highlighLng the discovery of key substrates for this phosphatase complex important for driving mitoLc exit, they also point at the main knowledge gaps such as the understanding of how dephosphorylaLons events are temporally ordered. In the second review, Archambault et al (Archambault et al., 2022) focus on the role of de-phosphorylaLon in the reformaLon of the nucleus: from the mechanisms involved in clustering the chromosomes together, to direct the deposiLon of membranes around the chromaLn, sealing the membranes and re-assembling the lamina and re-building the nuclear pore complexes. This thorough analysis clearly reveals that several Protein Phosphatase 1 (PP1) enzymes play a central role in the process but also that addiLonal funcLons of these and other phosphatases will almost surely emerge in the coming years.Our current understanding of the mechanisms that underpin successful cytokinesis largely stem from the use of a restricted number of model systems. IniLal studies oeen focused on early embryonic divisions in marine organisms (Rappaport, 1961;Rappaport, 1996). As Lme progressed these were complimented with the rise of more geneLcally tractable systems and advances in the ability to manipulate Lssue culture cells (D'Avino et al., 2015). However, the diversity of systems remained limited. Whilst these models have made an enormous impact on our understanding of the event that drive cytokinesis, it is becoming increasingly clear that they may only offer a small window into the molecular processes driving cell division. Two reviews in this collecLon bring together observaLons made in diverse models that highlight the need to invesLgate cell division in different cells and Lssues in order for us to gain a comprehensive understanding of the molecular events that drive all stages of cytokinesis. Ozugergin and Piekny (Ozugergin and Piekny, 2022) focus on the mechanisLc observaLons made in different Lssue culture systems that highlight subtle differences and the future need to expand our analysis beyond the work horse model of HeLa cells exploited by so many. In contrast, Gerhold et al (Gerhold et al., 2022) focus on the different modes of cell division within the germ line and in parLcular those where the division process is incomplete.Here they make a clear case of the future need to further study these parLal germ line divisions to gain new insight into how the different stages of cytokinesis are regulated. With the advent of new geneLc, molecular biology and microscopy tools and techniques that allow these addiLonal models to be exploited, we are on the cusp of an exciLng period of cytokinesis research that will reveal a much deeper understanding how the mechanism driving cell division.Finally, two arLcles review our current knowledge of the mechanisms involved in the final separaLon, or abscission, of the two daughter cells at the end of cytokinesis. Aeer compleLon of cleavage furrow ingression, the two daughter cells remain connected by an intercellular bridge (IB) which contains an organelle, the midbody, that acts as a plajorm for the recruitment and regulaLon of the proteins involved in the final scission event. Andrade and Echard (Andrade and Echard, 2022) elegantly and comprehensively review the mechanics and regulaLon of abscission in animal cells. They iniLally discuss the role of the tension generated at the IB and how, counterintuiLvely, high IB tension inhibits abscission. They describe the cellular and molecular components that contribute to IB tension and how they could regulate the acLvity and assembly of the ESCRT-III proteins, which mediate the final membrane fission event during abscission. In parLcular, they discuss how cytoskeletal proteins, membrane lipid composiLon, and membrane structures like caveolae contribute to IB tension and to its release necessary to trigger abscission. In the end, they also discuss whether the mechanisms that regulate abscission in cultured cells apply to all cell types, and how cells could potenLally "sense" IB tension. A second review arLcle discuss the role of integrins in cytokinesis and in maintaining genomic integrity (Rani et al., 2022). The authors discuss that integrin-mediated adhesion plays an important role in abscission in human cells by regulaLng the Lming of the recruitment to the midbody of the protein Cep55, which in turn is responsible for the recruitment of ESCRT-III components. This regulaLon seems to occur through premature degradaLon of the mitoLc kinase Plk1, which phosphorylated Cep55 to prevent its midbody localizaLon unLl compleLon of furrow ingression. InteresLngly, both arLcles also discuss how the process of "tracLon-mediated cytoplasmic fission" or "cytofission", which is not dependent on ESCRT-III, could represent an ancient mechanism of cell separaLon at the end of cytokinesis that could sLll be employed by some cell types in emergency situaLons to prevent tetraploidy and genomic instability.

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