Grant: Foundation Grant

Cancer is the leading cause of mortality in Canada representing 30% of all deaths. One in 2.3 individual will get cancer and 1 in ~3.8 will die from it, incurring $1.16 trillion in direct cost worldwide in 2010. Genomic instability is a common feature of tumor cells and is thought to represent a basic mechanism to acquire the several genetic alterations required during the neoplastic process. Double-strand breaks (DSBs), the most lethal kind of DNA lesions, can be repaired by two pathways; homologous recombination (HR) or non-homologous end-joining (NHEJ). The choice between NHEJ and HR involves an intricate network of resection enzymes whose interplay and hierarchy remain largely unexplored. It is becoming increasing clear that not only failure, but also misuse, of these pathways can trigger genomic instability leading to cancer, the biggest killer in Canada. Paradoxically, defects in the DSB pathways provide weaknesses that can be exploited to design new targeted cancer therapies. The DSB repair machinery can thus be seen as a double-edged sword in cancer protection and treatment, making the understanding of its regulatory mechanisms of crucial importance in the cancer research field. This proposal aims to obtain a comprehensive view of the functions of HR enzymes. By funding this Foundation Program, it will ensure that the mechanisms of these enzymes are defined. Furthermore, using novel inhibitors discovered by our group, we will inhibit the functions of these enzymes to target the vulnerabilities of cancer cells to improve patient care.