Abstract
Telomerase ribonucleoprotein was discovered over three decades ago as a specialized reverse transcriptase that adds telomeric repeats to the ends of linear eukaryotic chromosomes. Telomerase plays key roles in maintaining genome stability; and its dysfunction and misregulation have been linked to different types of cancers and a spectrum of human genetic disorders. Over the years, a wealth of genetic and biochemical studies of human telomerase have illuminated its numerous fascinating features. Yet, structural studies of human telomerase have lagged behind due to various challenges. Recent technical developments in cryo-electron microscopy have allowed for the first detailed visualization of the human telomerase holoenzyme, revealing unprecedented insights into its active site and assembly. This review summarizes the cumulative work leading to the recent structural advances, as well as highlights how the future structural work will further advance our understanding of this enzyme.
Highlights
In the 1930s, the natural ends of chromosomes were independently discovered in maize and fruit flies by McClintock and Muller, respectively [1,2,3]
The ‘terminal transferase’ responsible for synthesizing this sequence was subsequently discovered in Tetrahymena cell extract by Greider and Blackburn [10] and named telomerase
De novo synthesis of telomeric repeats at chromosome ends by telomerase requires both the reverse transcriptase activity of telomerase reverse transcriptase (TERT) subunit and an internal RNA template embedded within telomerase RNA (TER or hTR in humans)
Summary
In the 1930s, the natural ends of chromosomes were independently discovered in maize and fruit flies by McClintock and Muller, respectively [1,2,3]. De novo synthesis of telomeric repeats at chromosome ends by telomerase requires both the reverse transcriptase activity of telomerase reverse transcriptase (TERT) subunit and an internal RNA template embedded within telomerase RNA (TER or hTR in humans). The 30 RNA hairpin of the hTR H/ACA domain possesses a motif within its terminal stem loop named CAB box, which binds the Cajal body localization factor, TCAB1 (Figure 1B,C) [46,47].
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