Molecular mechanisms safe-guarding genome stability and preventing cancer during mammalian cell division

Faithful cell division ensures the correct segregation of the genetic material over multiple generations. Failure of this process may result in cell death or lay the foundation for tumorigenesis. An important prerequisite for successful chromosome segregation and maintenance of genomic integrity is the correct attachment of the chromosomes to microtubules, enabling faithful partitioning of the genetic material. The fidelity of this process is achieved through the combined actions of the so-called error correction process and the spindle assembly checkpoint, crucial molecular safe-guarding mechanisms that jointly eliminate erroneous microtubule-kinetochore attachments and promote bipolar chromosome orientation critical for faithful cell division. In my research group, we aim to understand the molecular mechanisms underpinning the accurate segregation of the chromosomes in mammalian cells, and what aspects of these processes are changed in cancer cells which often have higher, aneuploid, numbers of chromosomes than their non-transformed counterparts. Dynamic phosphorylation is a particularly important control mechanism for the cell division process. We have recently discovered distinct roles for specific mitotic kinase-phosphatase modules in the regulation of microtubule-kinetochore attachment formation, the spindle assembly checkpoint and the metaphase-to-anaphase transition^1-6, and now seek to further understand their actions and interplay with microtubules and kinetochores by using a combination of biochemical and cell biological techniques, including quantitative fixed and live cell imaging, CRISPR/Cas9-mediated genetic manipulation of cells, in vitro reconstitution assays and protein-protein interaction analysis by mass spectrometry.