Regulation of Human Telomerase Assembly and Recruitment to Telomeres

Telomerase is the ribonucleoprotein complex that synthesizes telomeric repeats and maintains telomere length in cells where it is expressed. The telomerase holoenzyme is composed of many regulatory factors which instruct telomerase biogenesis and engagement with telomeres. Common themes of telomerase regulation in divergent organisms emerge in the form of telomerase RNA accumulation, trafficking among cellular compartments, and cell cycle dependent access to telomeres. My investigations have focused on human telomerase regulation. I found that a key chaperone which localizes telomerase to Cajal bodies binds and releases telomerase in a cell cycle dependent fashion in coordination with the increased accessibility of telomeres during the replication phase (Chapter two). I also investigated the role of the canonical H/ACA small nucleolar RNA pathway in human telomerase maintenance of telomeres. I found that the H/ACA pathway was required for endogenous telomerase to assemble into active enzyme and that chaperone trafficking of telomerase to Cajal bodies regulated telomere length homeostasis, but was not a requirement for telomere maintenance (Chapter Three