Grant: Project Grant

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 DNA resection enzymes in the DSB pathway choice. Our goal is then to use this knowledge to understand the roles of these proteins in genome stability. Furthermore, using novel inhibitors discovered by our group, we aim to inhibit the functions of these enzymes in cancer cells to potentiate radiotherapy and chemotherapy.