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Review
. 2016 Sep 14;7(9):64.
doi: 10.3390/genes7090064.

Telomerase Regulation from Beginning to the End

Deanna Elise MacNeil  1   2 , Hélène Jeanne Bensoussan  3   4 , Chantal Autexier  5   6   7
Affiliations
Review

Telomerase Regulation from Beginning to the End

Deanna Elise MacNeil et al. Genes (Basel). .

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.

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Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the writing of the manuscript, and in the decision to publish the manuscript.

Figures

Figure 1
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
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.
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