Grant: Operating Grant

Cancer is the leading cause of premature death in Canada and the Canadian Cancer Society has estimated that one out of every four Canadians is expected to die from cancer. Understanding molecular events leading to cancer will provide crucial knowledge for the design of anti-cancer therapeutics. A hallmark of cancer is genome instability, which can arise from disruption in telomere maintenance and genomic integrity. Telomeres are heterochromatic structures found at the ends of linear eukaryotic chromosomes, which function to protect the natural chromosome ends from being recognized as damaged DNA, thereby helping maintain genomic integrity. Telomere repeat binding factor 1 (TRF1), a component of the shelterin complex composed of five other protein subunits, plays an important role in the maintenance of telomere length and structure. TRF1 is a negative mediator of telomerase-dependent telomere length maintenance, which is activated in over 80% of human cancers. A telomerase inhibitor is currently in clinical trials. TRF1 is subjected to extensive post-translational modification including phosphorylation. In this proposal, we aim to investigate the mechanism by which phosphorylation regulates the function of TRF1. Knowledge gained from the proposed studies on TRF1 is expected to aid in the design of anti-cancer therapeutics and treatment of cancer patients.