Mitotic regulation of chromosome partitioning and cell division

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During cell division, chromosomes are faithfully duplicated and segregated, so that one copy of each chromosome can be inherited by the two daughter cells, which must carry identical genetic information. The fidelity of chromosome transmission has important medical implications. For example, aberrant chromosome numbers in eggs or sperms generate embryos that undergo spontaneous miscarriage or that have severe pathologies, such as the Down syndrome. Inaccurate genome partitioning during any of the millions of cell divisions taking place in our body can lead to tumour development.
Our laboratory studies the surveillance mechanisms that act during mitosis to ensure proper genome partitioning, using the budding yeast Saccharomyces cerevisiae as a model organism. Particularly, we focus on two aspects of mitosis that are crucial for preventing aneuploidy formation:

  1. how faithful chromosome segregation is overseen by the spindle assembly checkpoint (SAC) that monitors the correct attachment of chromosomes to the mitotic spindle;
  2. how mitotic exit and cytokinesis are regulated to preserve genome stability.

Mechanisms sustaining the Spindle Assembly Checkpoint (SAC)
The SAC prevents anaphase when errors occur during the bi-orientation of chromosomes on the mitotic spindle. By delaying sister chromatid separation and mitotic exit, the SAC gives to the cell the time necessary to establish the appropriate connections between kinetochores and microtubules, thus ensuring balanced chromosome partitioning. Once all chromosomes are bi-oriented, the SAC is turned off, allowing anaphase to take place.
Despite its importance, SAC-induced cell cycle arrest is transient. Moreover, if the SAC remains activated for a prolonged time, cells will escape mitotic arrest and adapt, through a process known as “mitotic slippage”. Mitotic slippage is thought to be a major cause of resistance of cancer cells to chemotherapeutic compounds that interfere with microtubule dynamics.
Despite the profound implications of mitotic slippage for human health, the factors influencing its speed and efficiency are largely unknown. In our laboratory we use genetic screens to identify novel genes involved in this process and to characterize the molecular mechanism(s) through which they control slippage.

Regulation of septin dynamics during cytokinesis
Growing evidence indicates that polyploid cells are genetically unstable and frequently undergo chromosome missegregation and aneuploidy, eventually leading to cancer development. Cytokinesis failure is a common mechanism leading to polyploidy.
In many animal cells and fungi, cytokinesis requires septins and a contractile actomyosin ring. In yeast, septins form a ring at the division site throughout most the cell cycle. However, the septin ring dynamics changes during the cell cycle. Particularly, just prior to cytokinesis, a spectacular remodelling of the septin ring occurs. This involves its splitting in two separate rings that sandwich the constricting actomyosin ring. Our laboratory is trying to identify and characterize, through genetic and proteomic approaches, the molecular determinants that mediate the septin ring dynamic transitions during the cell cycle.

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Simonetta Piatti

Members of the team

  • Giorgia BENZI
    (PhD Student) +33 (0)4 34 35 95 46
  • Alain DEVAULT
    (Staff Scientist) +33 (0)4 34 35 95 46
  • Sandy IBANES
    (Research Assistant) (+33) 04 34 35 95 45
  • Simonetta PIATTI Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 46
  • Antonella RUGGIERO
    (Post-Doc) +33 (0)4 34 35 95 45
    • 2018

      Recruitment of the mitotic exit network to yeast centrosomes couples septin displacement to actomyosin constriction.

      Tamborrini D, Juanes MA, Ibanes S, Rancati G, Piatti S.

      Nat Commun. 9(1):4308. Pubmed

    • 2017

      Asymmetric Localization of Components and Regulators of the Mitotic Exit Network at Spindle Pole Bodies.

      Scarfone I, Piatti S.

      Methods Mol Biol. 1505:183-193. Pubmed

    • 2016

      Control of Formin Distribution and Actin Cable Assembly by the E3 Ubiquitin Ligases Dma1 and Dma2.

      Juanes MA, Piatti S.

      Genetics. 204:205-20. Pubmed

    • 2016

      The final cut: cell polarity meets cytokinesis at the bud neck in S. cerevisiae.

      Juanes MA, Piatti S.

      Cell Mol Life Sci. 73:3115-36. Pubmed

    • 2015

      Asymmetry of the budding yeast Tem1 GTPase at spindle poles is required for spindle positioning but not for mitotic exit.

      Scarfone I, Venturetti M, Hotz M, Lengefeld J, Barral Y, Piatti S.

      PLoS Genet. 11:e1004938. Pubmed

    • 2015

      Coupling spindle position with mitotic exit in budding yeast: The multifaceted role of the small GTPase Tem1.

      Scarfone I, Piatti S.

      Small GTPases. 6:196-201. Pubmed

    • 2015

      Rho1- and Pkc1-dependent phosphorylation of the F-BAR protein Syp1 contributes to septin ring assembly.

      Merlini L, Bolognesi A, Juanes MA, Vandermoere F, Courtellemont T, Pascolutti R, Séveno M, Barral Y, Piatti S.

      Mol Biol Cell. 26:3245-62. Pubmed

    • 2013

      Budding yeast greatwall and endosulfines control activity and spatial regulation of PP2A(Cdc55) for timely mitotic progression.

      Juanes MA, Khoueiry R, Kupka T, Castro A, Mudrak I, Ogris E, Lorca T, Piatti S.

      PLoS Genet. 9(7):e1003575. Pubmed

    • 2013

      Yeast haspin kinase regulates polarity cues necessary for mitotic spindle positioning and is required to tolerate mitotic arrest.

      Panigada D, Grianti P, Nespoli A, Rotondo G, Castro DG, Quadri R, Piatti S, Plevani P, Muzi-Falconi M.

      Dev Cell. 26(5):483-95. Pubmed

    • 2012

      Budding yeast dma proteins control septin dynamics and the spindle position checkpoint by promoting the recruitment of the Elm1 kinase to the bud neck.

      Merlini L, Fraschini R, Boettcher B, Barral Y, Lucchini G, Piatti S.

      PLoS Genet. 8(4):e1002670. Pubmed

    • 2012

      Role of the Mad2 dimerization interface in the spindle assembly checkpoint independent of kinetochores.

      Mariani L, Chiroli E, Nezi L, Muller H, Piatti S, Musacchio A, Ciliberto A.

      Curr Biol. 22(20):1900-8. Pubmed

    • 2011

      Analysis of the rpn11-m1 proteasomal mutant reveals connection between cell cycle and mitochondrial biogenesis.

      Esposito M, Piatti S, Hofmann L, Frontali L, Delahodde A, Rinaldi T.

      FEMS Yeast Res. 11(1):60-71. Pubmed

    • 2011

      The mother-bud neck as a signaling platform for the coordination between spindle position and cytokinesis in budding yeast.

      Merlini L, Piatti S.

      Biol Chem. 392(8-9):805-12. Pubmed

    • 2010

      The RSC chromatin-remodeling complex influences mitotic exit and adaptation to the spindle assembly checkpoint by controlling the Cdc14 phosphatase.

      Rossio V, Galati E, Ferrari M, Pellicioli A, Sutani T, Shirahige K, Lucchini G, Piatti S.

      J Cell Biol. 191(5):981-97. Pubmed

    • 2010

      Adapt or die: how eukaryotic cells respond to prolonged activation of the spindle assembly checkpoint.

      Rossio V, Galati E, Piatti S.

      Biochem Soc Trans. 38(6):1645-9. Pubmed

    • 2009

      Cdc14 inhibition by the spindle assembly checkpoint prevents unscheduled centrosome separation in budding yeast.

      Chiroli E, Rancati G, Catusi I, Lucchini G, Piatti S.

      Mol Biol Cell. 20(10):2626-37. Pubmed

    • 2008

      The spindle position checkpoint: how to deal with spindle misalignment during asymmetric cell division in budding yeast.

      Fraschini R, Venturetti M, Chiroli E, Piatti S.

      Biochem Soc Trans. 36(Pt 3):416-20. Pubmed