Chromosome segregation, aneuploidy and cancer

An important source of the genomic damage associated with both aging and cancer is the accumulation of aneuploidies due to chromosome missegregation. In healthy cells, accurate chromosome segregation is normally ensured by the spindle assembly checkpoint. By contrast, in cancer cells, the spindle checkpoint fails to prevent abnormal segregation events, leading to highly aneuploid genomes. But how do cancer cells tolerate and proliferate despite these abnormal genomes? To understand this, a major interest of the lab focuses on p38-dependent stress response pathway that activates the p53 tumour suppressor in response to dramatic changes in gene dosage. Our second major interest is based on the fact that several widely used anti-cancer drugs and 2nd chemotherapeutics kill cancer cells by activating the SAC. But how does a prolonged mitotic arrest lead to cell death? To understand this we are dissecting the factors that dictate the balance between “death in mitosis” and “slippage”, whereby cells exit mitosis, return to interphase and survive. A genome-wide siRNA library screen has identified a transcription factor that plays a key role promoting “death in mitosis”. We are now delineating the apoptosis pathways that connect this transcription factor with mitotic cell death. For more information on the lab, see www.bub1.com.