Abstract
To gain understanding of the physiological mechanisms that direct telomerase biogenesis and regulation, we purified endogenously assembled Tetrahymena telomerase holoenzyme using epitope-tagged TERT. Together, the results of molecular, genetic and biochemical assays define a holoenzyme complex containing telomerase RNA, TERT, p75, p65 and p45 subunits. Each subunit has an essential, non-redundant function in telomerase-mediated telomere maintenance. Genetic depletion of any subunit results in telomere shortening, but a division of labor among the subunits emerges from a comparison of their impact on telomerase holoenzyme biogenesis. One Tetrahymena telomerase holoenzyme subunit, p65, is an RNP biogenesis factor required for assembly of telomerase RNA and TERT. Two other subunits, p75 and p45, act to allow telomerase RNP function at telomeres. Our studies of the human telomerase holoenzyme have focused on the pathway of RNP biogenesis, which is defective in patients with the bone marrow failure syndrome dyskeratosis congenita. We are studying the RNA binding proteins that associate with the human telomerase RNA to direct processing of the precursor transcript and assembly of a stable RNP. Ultimately we hope to understand the functions of each holoenzyme subunit in biochemical detail and to elucidate the mechanisms underlying telomerase deficiency in disease.
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