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Chromosome Segregation

Director

Rosella Visintin

Activities

My laboratory is interested in understanding the molecular mechanisms that control cell division, the process by which a cell generates two genetically identical daughter cells. For this to occur, cells need to replicate their chromosomes and faithfully distribute each copy into the daughter cells. To ensure that each cell receives only one copy of each chromosome, cell cycle events need to be coordinated in time and space. If these mechanisms fail then genomic integrity is lost, which can lead to cell death or the acquisition of proliferation abnormalities. In particular, we focus on mitosis, the phase of the cell cycle during which replicated genomes are separated and packaged into daughter nuclei. We study chromosome segregation to better understand how errors made during this process contribute to the transformation of a healthy cell into a cancerous one.

  • Research projects

    Mitosis
    Mitosis is comprised of a highly choreographed sequence of events that lead to dramatic cellular reorganization. Although it is a continuous process, cytological changes allow it to be arbitrarily divided into sub-phases including prophase, prometaphase, metaphase, anaphase and telophase. Three major transitions take place during mitosis: 1) the G2/M transition, where entry into mitosis is controlled; 2) the metaphase-anaphase transition, at which sister chromatid separation is triggered; and 3) the M/G1 transition, at which cells reverse the processes that led to mitotic entry and reset the conditions for a new round of cell division. In higher and lower eukaryotes transitions 2) and 3) define mitotic exit. These are the focus of our laboratory.

    Metaphase-anaphase transition: Chromosome segregation
    To ensure the correct transmission of chromosomes during cell division, replicated chromosomes (sister chromatids) must first be separated and then segregated between the daughter cells. Sister chromatid segregation occurs in anaphase and is triggered by the dissolution of the cohesin complexes that hold the sister chromatids together. Cohesin is cleaved by separase whose activity is restrained by securin. Securin, in turn, is controlled by a surveillance mechanism, the spindle assembly checkpoint (SAC). The SAC is a signaling pathway that delays sister chromatid separation until all sister chromatids have correctly attached to the microtubules of the mitotic spindle. When the SAC is satisfied cells can proceed into anaphase. Progression through anaphase is mediated by mitotic spindle activities. A focus of the lab is to obtain a molecular understanding of the regulatory networks that control sister chromatid separation and spindle dynamics. We recently found a budding yeast mutant that cannot proceed through anaphase regardless of having degraded securin and cleaved cohesin. Elucidating the molecular defects characterizing our double mutant will allow us to define a novel pathway that is essential for sister chromatid segregation.

    M-G1 transition: Mitotic exit
    Mitotic exit initiates with the down-regulation of cyclin-dependent kinase (CDK) activity, a family of kinases whose activity controls cell cycle progression. Next, the phosphate groups that CDKs added to their targets to allow cells to enter mitosis must be removed so that the cells can exit mitosis. During my postdoctoral work in Dr. Amon’s laboratory I found that in budding yeast, the Cdc14 phosphatase is important for both CDK down-regulation and the reversal of mitosis-promoting phosphorylation events. We also showed that Cdc14 activity is controlled by changes in its subcellular localization. The phosphatase is sequestered in the nucleolus by its inhibitor Cfi1/Net1 for much of the cell cycle. At anaphase, two regulatory networks; the Cdc Fourteen Early Anaphase Release network (FEAR) and the Mitotic Exit Network (MEN) sequentially release Cdc14 from Cfi1. This sequential activation of Cdc14 triggers, in a wave-like manner, the dephosphorylation of distinct populations of CDK substrates and thus mitotic events at different stages of anaphase. Indeed the FEAR and MEN networks coordinate mitotic exit with different cell cycle events.
    When I started with my own laboratory I continued to work in this area of research because critically important questions regarding the control of exit from mitosis have remained unanswered. In particular, I wished to (1) Determine how Cdc14 becomes inactivated after completion of mitotic exit, and (2) Understand how the Cdc14-Cfi1 interaction is regulated.

  • Publications

    • Visintin R. (2011). Cdc14B: when a good kid turns bad. Cell Cycle 10:2416-7.
    • Manzoni, R., Montani F., Visintin C., Caudron F., Ciliberto A., and Visintin R. (2010). Oscillations in Cdc14 release and sequestration reveal a circuit underlying mitotic exit. JCB, 190: 209-222.
    • De Wulf P., Montani F. and Visintin R. (2009). Phosphatases take the cell cycle stage. Current Opinion in Cell Biology, 21:806-15
    • De Wulf P. and Visintin R. (2008). Cdc14B and APC/C takle DNA damage. Cell, 134: 210-2
    • Visintin C., Tomson B.N., Rahal R., Paulson J., Cohen M., Taunton J., Amon A. and Visintin R.. (2008). Apc/C-Cdh1-mediated degradation of the Polo kinase Cdc5 promotes the return of Cdc14 into the nucleolus. Genes Dev, 22: 79-90


    All publications

  • Funding

    • Associazione Italiana per la Ricerca sul Cancro (AIRC)
    • Howard Hughes Medical Institute (HHMI)
    • Ministry of Health

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PARTNERSHIP

Università degli Studi di Milano Ecancer Medical Science IFOM-IEO Campus

CREDITS

Ministero della Salute Joint Commission International Breastcertification bollinirosa

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