Distinguished Lec

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BESE Distinguished Lecture Series - Professor Andrea Musacchio

Start Date: May 15, 2017
End Date: May 15, 2017

​​​TITLE: Cell division: learning from reconstitution
DATE: Monday, May 15, 2017
TIME: 11:00 a.m. - 12:30 p.m.
LOCATION: Lecture Hall Level 0 · between Buildings 2 & 3

During mitotic cell division, each daughter cell receives from its mother cell an exact, full copy of the genome. For this to happen, the sister chromatids in the mother cell must bi-orient on the mitotic spindle. Sister-chromatid separation at the metaphase-to-anaphase transition then leads to equal segregation of the genome to the two daughters. Chromosome attachment to microtubules takes place at complex protein structures named kinetochores, which contain multiple copies of as many as ~30 individual core subunits, as well as a vast array of regulatory subunits. In the last several years, our laboratory engaged in the reconstitution and structural characterization of several kinetochore subcomplexes that operate at the interface with microtubules. Highlights of this work were the reconstitution of the subunits of the chromatin-distal Knl1 complex, Mis12 complex, Ndc80 complex (KMN) network, a 10-subunit super-complex that mediates microtubule binding and mitotic checkpoint control. These studies began to shed light on the structural organization on the KMN network and how it reflects on microtubule binding. Recently, we extended our efforts to the reconstitution of the chromatin-proximal components. We are therefore for the first time in a position to address the core kinetochore structure to reveal its plan of assembly and its principal functional features. Kinetochores also determine the timing of mitotic exit by exercising control over the cell cycle machinery. This control is exercised by a cell cycle checkpoint named the spindle assembly checkpoint (SAC), and aims to prevent premature mitotic exit in presence of unattached chromosomes. We have reconstituted SAC signalling in vitro and identified a rate-limiting step in the pathway, as well as a set of catalysts that relieve it. We are currently assessing the role of kinetochores in SAC signalling, using reconstituted material as our entry point in the investigation.

Andrea Musacchio (born 1964) graduated in Biology from the Tor Vergata University of Rome in 1990, working for his undergraduate degree with Prof. Giovanni Cesareni on the development of phage display libraries. Musacchio later moved to the European Molecular Biology Laboratory in Heidelberg to carry out his PhD work in the area of biochemistry and structural biology under the supervision of the late Dr. Matti Saraste. After receiving his PhD title from the University of Heidelberg early in 1995, Musacchio moved to the Harvard Medical School to work as a postdoctoral fellow in the laboratory of Prof. Stephen C. Harrison, supported by Human Frontier Science Program and the American Cancer Society postdoctoral fellowships. In Boston, Musacchio worked on the structural characterization by X-ray crystallography and electron microscopy of protein machinery implicated in membrane trafficking. Early in 1999, Musacchio gained independence at the European Institute of Oncology in Milan, where he started directing a research group investigating the molecular mechanisms of chromosome segregation during mitosis. In 2011, Musacchio moved to Dortmund to direct the Department of Mechanistic Cell Biology at the Max Planck Institute of Molecular Physiology. Since 2012, he is also Honorary Professor at the University of Duisburg-Essen. Musacchio authored approximately 130 research papers, is EMBO Member since 2009, and has been awarded two consecutive advanced ERC awards. The most characteristic mark of the Musacchio laboratory is the conjugation of diverse approaches, including biochemistry, structural biology, and cell biology, to the study of chromosome segregation. In particular, the Musacchio laboratory addressed the mitotic checkpoint and its crucial role in ensuring that chromosome segregation during mitosis occurs without loss or gain of chromosomes in the daughter cells. This checkpoint pathway operates at kinetochores, cellular structures that mediate the capture of microtubules during preparation for cell division. The overarching aim of the laboratory is to reconstitute kinetochore-microtubule attachment and its feedback control in vitro entirely with purified components.