The Structural Mechanism of Human Telomerase RNA Domains and Premature Aging-Related Disease Mutants (2009)

Undergraduates: Courtney Slough, Vijay Sekaran

Faculty Advisor: Michael B. Jarstfer
Department: Chemistry

---

Telomerase is a ribonucleoprotein complex involved in the addition of six nucleotide repeats to telomeric DNA at the end of our chromosomes subsequently controlling cellular lifespan. Important to enzyme activity is the human telomerase RNA (hTR), whose diverse secondary structure is intrinsic for biological function. Mutations in the human telomerase RNA (hTR) primary sequence have been linked to premature aging-related diseases such as aplastic anemia (AA) and the autosomal dominant form of dyskeratosis congenita (DKC). Previous experiments have demonstrated that these mutations affect hTR stability and diminish overall telomerase activity, though structural consequences are completely unknown. We propose that examining the solution structure of individual domains of both wild-type hTR and disease-related mutants via the high resolution, single nucleotide approach selective 2´-hydroxyl acylation analyzed by primer extension (SHAPE) will identify if RNA sequence mutations cause structural reorganization. By determining the hTR domain native conformation and effects of mutations on RNA architecture, we will illustrate the biological importance of individual RNA motifs in the context of the telomerase holoenzyme and illuminate the mechanism of AA and DKC disease etiology.