Physiological assembly and activity of human telomerase complexes

Abstract

Telomerase is a specialized reverse transcriptase conserved throughout almost all eukaryotic life. It plays a fundamental role in genome maintenance, adding back the telomeric DNA repeats lost from chromosome ends due to incomplete replication or damage. The protein and RNA subunits of telomerase fold and function in a co-dependent manner to establish a high fidelity of telomeric repeat synthesis. Over the past two decades, studies of telomerase have uncovered previously unanticipated levels of complexity in its assembly, activity and regulation. This review describes the current understanding of telomerase in humans, with particular focus on telomerase biogenesis and regulation in its cellular context.

Figure 1. Motifs and domains of human telomerase RNA and telomerase reverse transcriptase

A. The secondary structure of the 451-nucleotide mature hTR molecule is depicted. Boxes or brackets indicate the locations of motifs involved in telomerase RNP biogenesis (the H/ACA motif and BIO box), hTERT binding or intranuclear localization (the CAB box). Note that the second half of the molecule, the independently stable H/ACA domain, resembles a snoRNA. B. A putative architecture of hTERT is depicted with the suggested function of each domain.

Figure 2. Biogenesis pathway for human telomerase RNA and telomerase RNP

A. An ordered series of RNA processing steps is required for production of mature hTR from the precursor synthesized by RNA Polymerase II. Precedents from studies of other nuclear RNPs suggest that the biochemical steps listed are likely coupled with steps of RNP transport between cellular compartments. Which biogenesis steps involve the hTR BIO box or the dyskerin surface defined by X-linked DC mutations are not yet known. B. An ordered series of RNP assembly steps is required for production of functional telomerase RNP. Assembly of hTR with the H/ACA-motif binding proteins (in green) dyskerin, NHP2 and NOP10 is essential for its accumulation in vivo. These proteins recruit the fourth shared H/ACA-motif binding protein GAR1. RNP assembly on the hTR H/ACA motif would be predicted to influence the relative orientation of the hTR binding surfaces for hTERT (in blue), potentially promoting hTR-hTERT interaction. The numerous proteins that are proposed to regulate human telomerase function in vivo (in yellow) may interact with the catalytically active hTERT RNP and/or with telomerase RNP or hTERT assembly intermediates. This schematic is intended as a visual aid, not an accurate three-dimensional representation of a model for human telomerase RNP architecture.