UCSF

Telomerase is a ribonucleoprotein that adds telomeric DNA to the ends of linear chromosomes. It is composed of two core components, the reverse transcriptase component, hTERT, and the RNA template, hTR. In the absence of sufficient telomerase, most differentiated cells experience telomere shortening with each cell division and eventually undergo replicative senescence. Conversely, stem cells and the majority of cancer cells have high telomerase activity, which maintains telomere length allowing them to divide indefinitely. While the role of telomerase in telomere maintenance is clear, recent studies have suggested non-canonical roles for telomerase. The purpose of this thesis is to investigate any non-canonical roles for telomerase in both normal and cancer cells.

The first part of this thesis focuses on the role of telomerase in primary human T cells. T cells are one of the few types of differentiated cells that upregulate telomerase activity upon stimulation. While telomerase activity and T cell proliferation correlate, it is unknown if this upregulation is necessary or even quantitatively coupled to T cell survival. Suprisingly, I find that the telomerase RNA, hTR, actually protects CD4+ T cells from apoptosis independent of telomere maintenance or telomerase activity. This is the first report showing a non-telomere role for the telomerase RNA.

The second part of this thesis investigates a controversial mechanism for a non-canonical role for hTERT in Wnt signaling. One study published that telomerase activity promotes Wnt/β-catenin signaling in mice and HeLa cells. However, another study was unable to reproduce these findings in mice, but did not investigate these findings in cancer cells. Since Wnt signaling is often dysregulated in breast cancer, we sought to determine if we could independently replicate any hTERT -Wnt/β-catenin interactions in breast cancer cells. Using genetic, biochemical, and bioinformatic analyses we do not find any data supporting the hypothesis that hTERT promotes Wnt/β-catenin signaling in breast cancer cells and instead suggest that any published interactions detected are cell line and cell context specific.

We and others have shown hTERT can promote proliferation, protect from apoptosis, and promote mitochondrial function independent of telomere maintenance and/or telomerase activity in a wide variety of cell types. This thesis shows that hTERT does not promote these functions through Wnt/β-catenin signaling. Furthermore, I show for the first time that hTR also has a non-telomere and non-telomerase role protecting from apoptosis in CD4+ T cells. While the importance of telomerase for maintaining telomeres is clear, this thesis shows that both of the telomerase core components have non-canonical roles in cell survival in normal and cancer cells.