Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase.

Inhibition or activation of the reverse transcriptase telomerase can profoundly affect the proliferative capacity of normal cells and cancers. Here, we elucidate structural requirements for function of the essential RNA component of human telomerase, hTR. Two motifs within the independently stable H/ACA domain of hTR are required for accumulation of the mature RNA in vivo. However, these motifs can be substituted by a heterologous H/ACA family RNA. Two additional hTR elements are required both in vivo and in vitro for telomerase catalytic activity. Surprisingly, each of these elements independently binds to the telomerase reverse transcriptase. Our results establish fundamental differences between vertebrate and ciliate telomerase ribonucleoprotein architectures and also suggest strategies for the pharmaceutical development of telomerase-based anticancer therapies.