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Feedback control of cell division

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Our work focuses on kinetochores, large proteinaceous structures that are built on the centromere region of chromosomes. In mitosis and in meiosis, kinetochores provide chromosomes with a site of attachment to spindle microtubules. They also control a cell cycle checkpoint, the spindle assembly checkpoint, required to prevent mitotic exit prior to the completion of chromosome bi-orientation. Biochemical reconstitution is playing a leading role in developing an understanding of kinetochore organization. In recent years, we have contributed to this effort by reconstituting several kinetochore sub-complexes that operate at the interface with microtubules, including the 4-subunit Ndc80 and Mis12 complexes, and the 2-subunit Knl1 complex. Whenever possible, we have been using high- or medium-resolution analysis to gain a structural understanding of these kinetochore complexes and have investigated the functional implications of our work. More recently, we have extended our efforts to include a significant set of additional kinetochore subunits that are positioned more internally in the kinetochore, at the interface with chromatin. I will report on these recent efforts. Understanding how kinetochores control dynamically the checkpoint response in relation to their attachment to microtubules is also an interesting and important challenge. We are therefore testing the ability of the reconstituted kinetochore complexes to interact with different checkpoint proteins. For instance, we are in the process of characterizing the complex interactions of the Bub1 and BubR1 proteins with Knl1, using Saccharomyces cerevisiae and human cells as model systems. In my seminar, I will report on these current efforts.

Last resort readings Petrovic A, Mosalaganti S, Keller J, Mattiuzzo M, Overlack K, Krenn V, De Antoni A, Wohlgemuth S, Cecatiello V, Pasqualato S, Raunser S & Musacchio A (2014) Modular Assembly of RWD Domains on the Mis12 Complex Underlies Outer Kinetochore Organization. Mol Cell 53:591-605. doi: 10.1016/j.molcel.2014.01.019. Krenn V, Overlack K, Primorac I, van Gerwen S & Musacchio A (2014) KI motifs of human Knl1 enhance assembly of comprehensive spindle checkpoint complexes around MELT repeats. Curr Biol 24:29-39. doi: 10.1016/j.cub.2013.11.046. Primorac I, Weir JR, Chiroli E, Gross F, Hoffmann I, van Gerwen S, Ciliberto A & Musacchio A (2013) Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling, Elife 2:e01030. doi: 10.7554/eLife.01030.

This talk is part of the MRC LMB Seminar Series series.

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