Grant: CIHR New Investigator

Aneuploidy is a genetic state defined by an abnormal number of chromosomes. It is caused by aberant cell division and is the most common genetic affliction in man. It is the primary cause of miscarriage; approximately 30% of spontaneous abortions exhibiting aneuploidy. Down Syndrome, which is caused by aneuploidy of chromosome 21 (3 instead of 2 copies) is the most common aneuploidy found in newborns affecting a staggering 1/800-1/1000 births. In cancers, aneuploidy is the most common genetic trait. Although the detrimental effects of aneuploidy to human health have been long recognized, the molecular mechanisms that result in aneuploidy remain poorly understood. Aneuploidy is prevented by cell cycle checkpoints that detect errors in, and halt cell division processes until these errors are corrected. One such mechanism, known as the SAC or spindle Assembly Checkpoint functions during cell division to ensure equal segregation of chromosomes, thus preventing aneuploidy. This project aims to understand the regulation of a small but essential group of enzymes that regulate the chromosome division process, and thus play a pivotal role in preventing cancer and other chromosome based diseases. In particular, the catalytic function of these enzymes is poorly understood, and how they are regulated during the different stages of cell division remains unclear. Importantly, misregulation of this activity is a known cause of chromosome segregation errors and thus aneuploidy. Determining how these enzymes regulate targets and are themselves regulated by the fundamental biological process of cell division is critical for understanding the basis of the wide range of chromosome-based genetic diseases. Morover, there has been increasing interest recently in targetting these enzymes as a means of therapeutic intervention, and the work proposed here will facilitate the discovery of novel targets for aneuploidy based diseases, as well as the generation of novel therapeutics.