Grant: Operating Grant

Aneuploidy is a genetic state defined by an abnormal number of chromosomes. It is caused by aberrant cell division and is the most common genetic affliction in man. It is the primary cause of miscarriage, with approximately 30% of spontaneous miscarriages exhibiting aneuploidy. Aneuploidy is also linked to mental and physical anomalies in newborns. In cancers, aneuploidy is the most common genetic trait. Although the detrimental effects of aneuploidy to foetal and 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 mitosis to ensure equal segregation of chromosomes to daughter cells, thus preventing aneuploidy. This project aims to understand the regulation of a small but essential group of enzymes that control both the SAC itself, as well as the chromosome segregation machinery of the cell, and thus play a pivotal role in preventing aneuploidy. 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 wide range of chromosome-based genetic diseases ranging from spontaneous abortions and infertility, to cancer and aging. Moreover, there has been increasing interest recently in targeting these enzymes as for cancer therapy. The work proposed here will facilitate the discovery of both biomarkers and novel targets for aneuploidy based diseases, as well as the generation of novel therapeutics.