Human telomerase: biogenesis, trafficking, recruitment, and activation

Abstract

Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species.

Keywords: biogenesis; cancer; recruitment; telomerase; telomere; trafficking.

Figure 1.

Functional domains of hTR and hTERT. (A) Secondary structure of the hTR. The pseudoknot and CR4/CR5 domains interact with the hTERT. The template for telomeric repeat synthesis is indicated. Two copies of the H/ACA complex, each composed of dyskerin, NHP2, NOP10, and GAR1, associate with the H/ACA domain of hTR to stabilize the RNA in the nucleus. TCAB1 interacts with the CAB box to facilitate telomerase localization to Cajal bodies. (B) hTERT contains four functional domains. The telomerase N-terminal (TEN) domain participates in catalysis and drives telomerase localization to telomeres. The TR-binding domain (TRBD) interacts with hTR. The reverse transcriptase (RT) and C-terminal extension (CTE) form the catalytic core of telomerase. Bar, 100 amino acids.

Figure 2.

Telomerase assembly, maturation, and recruitment to telomeres. hTERT is synthesized in the cytoplasm and associates with the chaperones HSP90 and p23. hTR cotranscriptionally binds dyskerin, NOP10, NHP2, and NAF1, with NAF1 subsequently being replaced by GAR1. Assembly of hTR and hTERT into catalytically active telomerase is aided by the AAA⁺ ATPases Reptin and Pontin. A question mark indicates that the subcellular location of assembly is still under investigation. Telomerase is recruited to CBs by its interaction with TCAB1. In S phase of the cell cycle, telomerase is recruited to telomeres by the interaction of the TEN domain of hTERT with the TEL (TPP1 glutamate [E] and leucine [L]-rich) patch of the OB-fold domain of the shelterin component TPP1.

Figure 3.

The telomerase catalytic cycle and its modulation by TPP1. Telomere extension requires multiple steps: primer DNA binding; extension of the primer using dGTP, TTP, and dATP as substrates; translocation of the RNA template relative to the active site and translocation of the DNA primer relative to the template; and recycling (thick arrow) for another round of extension. TPP1 aids translocation of the telomeric primer and reduces the rate of product dissociation from cycling telomerase to increase RAP.