Telomerase serves two independent and critical roles in normal stem cells and in cancer. Telomerase is reactivated in approximately 90% of human cancers, making telomerase one of the most commonly dysregulated pathways in human tumorigenesis. As a reverse transcriptase that synthesizes telomere repeats, telomerase maintains telomere length and stability to prevent the severe adverse consequences of telomere dysfunction, which include senescence, apoptosis and massive chromosome instability. In this role, telomerase supports the enormous proliferative capacity of both stem cells and cancer cells. In mediating the ability of cancer cells to proliferate in an immortal fashion, telomerase requires both TERT, the telomerase protein component, and TERC, the telomerase RNA component, which together add telomere sequences to chromosome ends. We recently identified a second function for TERT in facilitating the proliferation of quiescent, multipotent stem cells. This important new role for TERT in stem cell activation does not require TERC and is therefore independent of TERT's function in telomere synthesis. Thus, TERT acts in two discrete pathways - telomere synthesis and stem cell activation - that together are likely crucial for human cancer development. Despite the importance of TERT in these two critical pathways, TERT protein regulation remains poorly understood. The goal of this project is to understand TERT protein regulation, specifically how TERT protein stability is controlled. Consistent with its role as a critical regulator, we find that TERT protein is unstable, ubiquitinated and destroyed by the proteasome in human cells. Furthermore, we have employed powerful mass spectrometry tools to isolate a ubiquitin E3 ligase that specifically associates with TERT in human cancer cells. We propose: (1) To understand the role of destruction in regulating TERT protein function (2) To determine the function of the TERT-Associated Ubiquitin E3 Ligase (TAUL1) in TERT protein stability, cellular immortalization and cancer and (3) To understand the function of TAUL1 through analysis of a conditional knockout mouse.
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