Department of Biological and Medical Sciences

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  • Maintenance of correct chromosome numbers is absolutely critical for all living organisms. An evolutionarily conserved and self-monitoring surveillance system, the spindle assembly for the mitotic checkpoint (SAC) has therefore emerged to ensure the timely and high fidelity transmission of the genetic material to an offspring. In humans, failure of the SAC is a major determinant of age-related genetic disorders, of aberrant chromosome segregation and genome instability and represents the leading cause of pregnancy loss, birth and development defects.
     
    Recently considerable progress has been made in understanding the composition of the SAC and the recruitment hierarchy of its components. However, the molecular interactions of the SAC with the kinetochore have proved elusive, even though they are clearly indispensable for the accurate segregation of chromosomes. The understanding of the function and mode of regulation of this surveillance system requires definition of the structural details of the individual subunits and different subcomplexes. For this, we have exploited biochemical, biophysical, structural and cell biology methods including X-ray protein crystallography, NMR, small-angle X-ray scattering, surface plasmon resonance, analytical ultracentrifugation, isothermal calorimetry and ES-nanospray MS. The studies on the SAC and other signalling systems have shown that signalling assemblies often involve concerted folding and binding and cooperative interactions to give extended multiprotein assemblies. These have led to a general model for high signal-to-noise signalling involving weak binary interactions to well-defined but transient multiprotein assemblies. One long-term goal derived from the structural and functional definition of the SAC is to develop new therapies for the diagnosis and the treatment of human malignancies including cancer and age-related genetic disorders.
     
    In summary, understanding how sister genomes are separated with high fidelity to opposite poles of the cell is a matter of great interest in Biology and Medicine. The research area has clear potential for application in diagnostic and treatment of birth and developmental defects, cancer and human aging-associated disorders, which have a great impact for the well being and the Health and Biotechnology sectors.