Telomerase Regulation from Beginning to the End

Abstract

The vast body of literature regarding human telomere maintenance is a true testament to the importance of understanding telomere regulation in both normal and diseased states. In this review, our goal was simple: tell the telomerase story from the biogenesis of its parts to its maturity as a complex and function at its site of action, emphasizing new developments and how they contribute to the foundational knowledge of telomerase and telomere biology.

Keywords: H/ACA ribonucleoprotein; exosome; small Cajal body RNA; small nucleolar RNA; spliceosome; telomerase; telomere.

Figure 1

Schematic of human telomerase RNA (hTR) synthesis and processing. RNA polymerase II (RNAPII) read-through can generate 3′ extended hTR products, which need to be processed into mature hTR or degraded. (a) The H–ACA pre-RNP (ribonucleoprotein) complex involving dyskerin, NOP10, NHP2, and NAF1 co-transcriptionally assembles on the 3′ hairpin-hinge-hairpin-tail structure of hTR, possibly mediating RNAPII transcription termination. (a,b) The generation of shorter extended products versus longer extended products due to RNAPII read-through may be regulated by assembly of the H/ACA pre-RNP; (b) Defects in dyskerin–hTR interactions and RNP assembly lead to the generation of long extended hTR species, which can be exported to the cytosol for decapping mRNA 2 (DCP2)/ 5′-3′ Exoribonuclease 1 (XRN1) mediated degradation. It is possible that this export occurs in the absence of nuclear exosome targeting (NEXT) recruitment through 5′ cap-binding complex (CBCA), as NEXT is involved in the recruitment of the nucleolar Rrp6 exosome. b,c) The Rrp6-mediated human exosome may be involved in both maturation and degradation pathways for extended products, in conjunction with the micro-RNA processing component DGCR8. (d) Short extended products are targeted for processing by the canonical poly-adenylation machinery involving PAPα/γ in a poly(A) binding protein nuclear 1 (PABPN1) and polyadenosine-specific ribonuclease (PARN) dependent manner; (c) Shorter extended hTR species can also be targeted to the Rrp6 exosome through the addition of a shorter poly(A) tail by the Trf4/5-Air1/2-(TRAMP) complex, recruited by CBCA. The mechanism behind balancing Rrp6 exosome-mediated degradation and maturation remains inconclusive; (d) However, poly(A) tails added by the TRAMP complex may be extended by PAPα/γ to generate PABPN1/PARN processing targets. Given that CBCA is known to recruit TRAMP and repress PARN, the presence of CBCA at the pre-hTR species 5′ end may be relevant in mediating these pathways; (e) The structural domains of mature hTR are denoted in coloured boxes: the pseudoknot region in pink containing the template, P2b and P3 regions; P1b helix in green; CR4/5 domain in yellow containing the P6.1 stem-loop; and the CR7 domain in blue containing both the H/ACA and Cajal body (CAB) boxes.

Figure 2

Assembly and Localization of H/ACA Ribonucleoprotein Complex. (a) SHQ1 binds to free dyskerin in the cytoplasm and translocates to the nucleus; (b) The reptin/pontin hexamer binds the dyskerin–SHQ1 complex directly to both dyskerin and SHQ1; (c) promoting SHQ1 removal from dyskerin; (d) This promotes the recruitment of the four H/ACA RNP proteins, dyskerin, NAF1, Nop10 and NHP2 to the nascent hTR; (e) GAR1 displaces NAF1 through the formation of a heterodimer which in turn forms a pool of NAF1 homodimers; (f,g) The mature hTR gets recruited to the nucleolus where it assembles with hTERT which was previously processed by hsp90, p23 and the reptin/pontin hexamer; (h) This allows hTERT recruitment to the nucleolus to form a mature telomerase complex while bound to fibrillarin and nucleolin with the hTR; (i) Telomere Cajal body protein 1 (TCAB1) recognizes the Cajal body (CAB) box of the hTR in the mature telomerase complex and recruits it to the Cajal body; (j) In S-phase, the Cajal body will colocalize with telomeres and facilitate the recruitment of the mature telomerase complex to the telomeres.