The systems biology of mitotic checkpoint signaling and its relevance to cancer cell biology

Project Summary: The Spindle Assembly Checkpoint (SAC) is a cell cycle control that ensures accurate chromosome segregation during cell division. It is activated by unattached kinetochores, which recruit many different signaling proteins to produce an inhibitory signal that delays anaphase onset and averts chromosome missegregation. Aberrant SAC signaling has long been suspected to promote genome instability in cancerous cells, but the nature of the aberrations and their consequences remain unclear. We propose that the perturbation of SAC signaling dynamics can elevate chromosome missegregation. However, the SAC has been mainly studied under quasi stead-state conditions despite being a dynamical process. Therefore, we will tackle questions central to SAC signaling dynamics using a systems biological approach that integrates quantitative data and mathematical modeling. Our goal is to answer the following fundamental questions using a combination of experiments and theoretical modeling: What is the rate at which a single unattached kinetochore generates the ‘wait-anaphase’ signal? Does it change over the course of cell division? Is it sufficiently high to delay anaphase onset indefinitely? What are the main determinants of this rate? Answers to these questions will reveal a dynamical picture of SAC signaling and allow us to define the causes and consequences of aberrant SAC signaling in cancer cells.