Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

Human chromosome ends are protected from damage by a stretch of repetitive DNA sequences known as telomeres. In healthy mortal cells, telomere DNA is gradually shortened during successive rounds of replication as a cell ages, and therefore serves as a molecular clock. In cancerous cells the enzyme telomerase ensures maintenance of stable telomere length and therefore enables the indefinite growth and uncontrolled cell division characteristic of tumor formation. Telomerase activation requires both a protein and ribonucleic acid (RNA) component. In particular, proper incorporation of the RNA component is a complex multistep process that is not fully understood. In this proposal, we seek to understand the role that changes in the three dimensional structure of human telomerase RNA play in the process of telomerase activation. We hypothesize that recognition and modulation of an unusually stable structure in telomerase RNA, known as a G-quadruplex, is required for telomerase activation. To test this hypothesis, we will use an integrated experimental approach involving high-resolution structural biology, biophysical analysis, and in vivo functional methodologies to study the biological importance of the G-quadruplex structural element. Given the central role that telomerase plays in maintenance of telomere DNA in cancerous cells, we expect that a detailed investigation of its mechanism of activation will provide significant insight into the biology of several disease states. The results from our investigations will also offer the opportunity for the rational design of therapeutics that can specifically target the assembly of an enzyme essential for cancer cell progression.