Tuesday, 20 March 2018 at 11:00 | Large Operon, EMBL Heidelberg
Andrea Musacchio | Max Planck Institute of Molecular Physiology (DEU)
Host: Christian Häring, Cell Biology and Biophysics
Cell division: learning from reconstitution
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. Kinetochores also determine the timing of mitotic exit by exercising control over the cell cycle machinery through the spindle assembly checkpoint (SAC). The SAC coordinates completion of bi-orientation with the transition to anaphase, preventing premature mitotic exit in the presence of incompletely attached sister chromatid pairs. All SAC components are recruited to kinetochores and regulated there in a way that reflects attachment status but that remains poorly understood.
In the last several years, our laboratory engaged in the in vitro reconstitution and in the structural and functional characterization of several kinetochore sub-complexes that operate at the interface between chromatin and microtubules. We also reconstituted crucial aspects of SAC signalling, identifying a rate-limiting step in the pathway, as well as a set of catalysts that accelerate the accumulation of the checkpoint effector, the mitotic checkpoint complex (MCC).
Our current efforts aim to unravel the role of kinetochores in SAC signalling, using reconstituted material as our entry point in the investigation. I will report on the conceptual challenges associated with this idea, as well as on our recent experimental progress.
Andrea Musacchio 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 proteins implicated in trafficking of membrane and proteins in cells. Late 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 mitosis using a combination of structural, biochemical, and cell biological methods. In 2011, Musacchio moved to Dortmund to direct the Department of Mechanistic Cell Biology at the Max Planck Institute of Molecular Physiology. In 2012, he received an honorary professorship at the University of Duisburg-Essen.
The scientific interest of the Musacchio laboratory is the process of cell division. In particular, the laboratory studies the mitotic checkpoint and its crucial role in ensuring that chromosome segregation during mitosis is accurate, i.e that it occurs without loss or gain of chromosomes in the daughter cells. This 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. The most characteristic mark of the Musacchio laboratory is the conjugation of diverse approaches, including biochemistry, structural biology, and cell biology.