Cancer arises as a consequence of uncontrolled cell division. In healthy tissues, cell division is a well-controlled process during which both our duplicated genetic and cytoplasmic material is equally distributed over the two newly formed daughter cells, such that after a round of cell division each daughter cell has a complete set of 46 chromosomes. In marked contrast to normal cells, many human cancer cells have gained or lost whole chromosomes, i.e. these cells display numerical chromosomal instability and as a consequence have an aneuploid genome.
My group aims to understand at the molecular level how faithful chromosome segregation is normally ensured and why this segregation process is perturbed in cancer cells. We focus on a group of proteins termed the "chromosomal passenger complex" (CPC) that has a striking and unique localization pattern in the dividing cell. While initially present on chromosome arms and centromeres, right after chromosome segregation this complex moves from the chromosomes to the microtubules of the central spindle that signals where cytoplasmic division should start. As such this protein complex is in an excellent position to coordinate chromosome segregation with cytoplasmic division.
The chromosomal passenger complex consists of at least four interacting proteins: Aurora B, INCENP, Survivin and Borealin. While Aurora B is the enzymatic core of the complex, the other subunits somehow control its enzymatic activity and guide the enzyme to its specific locations in mitotic cell.
Research Questions
Using shRNA complementation, microscopy and chemical genetics we aim to address the following research questions:
- How is the chromosomal passenger complex targeted to its specific locations in the mitotic cell?
- How do the non-enzymatic subunits (e.g. INCENP, borealin and survivin) of the CPC control the function of Aurora B.
- How is Aurora B activity regulated in space and time?
- How does the CPC control the function of the mitotic checkpoint?
- What are the downstream substrates of the CPC?
By unwiring the workings of the chromosomal passenger complex we expect to gain novel insights into the origin of chromosomal instability in cancer cells.