Telomerase is the ribonucleoprotein complex that catalyzes the addition of telomere DNA repeats onto the 3'ends of linear chromosomes. Telomeres protect the ends of chromosomes from being recognized by the cellular DNA repair machinery as double strand breaks and also prevent end joining. In the absence of active telomerase, telomeres shorten with each round of DNA replication. Once a critical amount of telomere is lost, the cell enters replicative senescence and sometimes undergoes apoptosis. The high level of telomerase activity present in most cancers allows this roadblock to be avoided, making telomerase a potential drug target. Telomerase RNA and telomerase reverse transcriptase comprise the essential elements for telomerase activity in vitro. The goal of this fellowship will be to solve the high- resolution structure of medaka telomerase RNA P2ab in the catalytic core by NMR, investigate a potential of human telomerase RNA P2ab as a drug target to inhibit telomerase activity, and obtain small angle X- ray scattering structures of the medaka telomerase RNA both free and in complex with the telomerase reverse transcriptase.
The specific aims are to (1) investigate the structure, dynamics, and function of medaka telomerase RNA P2ab domain, (2) investigate human telomerase RNA J2a/b as a drug target to inhibit telomerase activity, (3) model medaka telomerase RNA using NMR and small angle X-ray scattering, (4) probe the structure and interactions between the medaka telomerase RNA and domains of the telomerase reverse transcriptase using small angle X-ray scattering and X-ray crystallography. These experiments will reveal the structure of the medaka telomerase RNA catalytic core and the intermolecular contacts between the RNA and the subdomain of the telomerase reverse transcriptase.
Telomerase, the RNA-protein complex responsible for maintaining telomeres, is highly active in cancer cells and inactive in most normal cells. This difference in activity is what makes telomerase a good target for anti-cancer drugs. The structure of the telomerase RNA and its interactions with the telomerase reverse transcriptase will not only provide a molecular basis for understanding telomerase activity, but also will guide future structure-based design of drugs against telomerase.