The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA-DNA hybrids

Akiyama, Benjamin M.; Parks, Joshua W.; Stone, Michael D.

doi:10.1093/nar/gkv406

Cited by 37 publications

(50 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In hTR, P2a.1 is an extension of P2a, and in medaka the putative P2a.1 hairpin is formed by J2a/3 loop residues. In both models the P2a.1 is close to or is in contact with the TEN domain, as suggested for human telomerase (12,52). In addition, in the model human TBE (P1 and its flanking single strands) is positioned in the groove formed by the T-CP motif of the TRBD so that the TBE can contact the TFLY motif of the TRBD directly (48).…”

Section: Resultsmentioning

confidence: 93%

Structural conservation in the template/pseudoknot domain of vertebrate telomerase RNA from teleost fish to human

Wang

Yesselman

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Telomerase is an RNA-protein complex that includes a unique reverse transcriptase that catalyzes the addition of single-stranded telomere DNA repeats onto the 3′ ends of linear chromosomes using an integral telomerase RNA (TR) template. Vertebrate TR contains the template/pseudoknot (t/PK) and CR4/5 domains required for telomerase activity in vitro. All vertebrate pseudoknots include two subdomains: P2ab (helices P2a and P2b with a 5/6-nt internal loop) and the minimal pseudoknot (P2b-P3 and associated loops). A helical extension of P2a, P2a.1, is specific to mammalian TR. Using NMR, we investigated the structures of the full-length TR pseudoknot and isolated subdomains in Oryzias latipes (Japanese medaka fish), which has the smallest vertebrate TR identified to date. We determined the solution NMR structure and studied the dynamics of medaka P2ab, and identified all base pairs and tertiary interactions in the minimal pseudoknot. Despite differences in length and sequence, the structure of medaka P2ab is more similar to human P2ab than predicted, and the medaka minimal pseudoknot has the same tertiary interactions as the human pseudoknot. Significantly, although P2a.1 is not predicted to form in teleost fish, we find that it forms in the full-length pseudoknot via an unexpected hairpin. Model structures of the subdomains are combined to generate a model of t/PK. These results provide evidence that the architecture for the vertebrate t/PK is conserved from teleost fish to human. The organization of the t/PK on telomerase reverse transcriptase for medaka and human is modeled based on the cryoEM structure of Tetrahymena telomerase, providing insight into function.T elomeres are the physical ends of linear chromosomes, composed of telomeric DNA and associated proteins. After each round of cell replication, telomeres shorten because of incomplete 3′-end replication of telomere DNA repeats and nucleolytic processing. Telomerase, a specialized reverse transcriptase, is a large ribonucleoprotein that plays essential roles in protecting the integrity of linear chromosomes in most eukaryotic species (1). Most somatic cells do not contain detectable telomerase activity, and consequently, after 40-60 cell divisions, their telomeres shorten below a critical length [∼12.8 repeats (2)] that leads to replicative senescence or to apoptosis (3). Most cancer cell lines, on the other hand, have significant telomerase activity, which continuously replenishes their telomeres and allows them to divide indefinitely; this dichotomy has made telomerase inhibition an attractive target for the development of anticancer drugs (4, 5). Mutations in human telomerase proteins and RNA cause a number of inherited diseases, such as autosomal dominant dyskeratosis congenita, idiopathic pulmonary fibrosis, myelodysplasia, and aplastic anemia (6-10).The telomerase holoenzyme consists of a unique reverse transcriptase protein (telomerase reverse transcriptase; TERT), which contains the active site for nucleotide addition, an essential telomerase RNA (...

show abstract

Section: Resultsmentioning

confidence: 93%

Structural conservation in the template/pseudoknot domain of vertebrate telomerase RNA from teleost fish to human

Wang

Yesselman

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In addition to binding the OB-fold domain of ACD for telomerase recruitment and RAP stimulation, the TEN domain supports the stable formation of the RNA–DNA duplex in the active site of the enzyme [142–144]. The reverse transcriptase and C-terminal domains of telomerase have also been proposed to interact with the telomeric DNA substrate to help promote RAP [145,146].…”

Section: Fundamental Mechanisms Of Telomerase Action In Yeasts and Mamentioning

confidence: 99%

Fundamental mechanisms of telomerase action in yeasts and mammals: understanding telomeres and telomerase in cancer cells

Armstrong

Tomita

2017

Open Biol.

View full text Add to dashboard Cite

Aberrant activation of telomerase occurs in 85–90% of all cancers and underpins the ability of cancer cells to bypass their proliferative limit, rendering them immortal. The activity of telomerase is tightly controlled at multiple levels, from transcriptional regulation of the telomerase components to holoenzyme biogenesis and recruitment to the telomere, and finally activation and processivity. However, studies using cancer cell lines and other model systems have begun to reveal features of telomeres and telomerase that are unique to cancer. This review summarizes our current knowledge on the mechanisms of telomerase recruitment and activation using insights from studies in mammals and budding and fission yeasts. Finally, we discuss the differences in telomere homeostasis between normal cells and cancer cells, which may provide a foundation for telomere/telomerase targeted cancer treatments.

show abstract

“…The single-stranded region on the 3′ side of the template wraps around the CTE (thumb domain), threading between the CTE and TEN domain but has no apparent anchor (Figure 5 b , e ). The TEN domain is positioned such that the sstDNA–template duplex could butt up against it at the end of a telomere repeat synthesis and play a role in strand separation (Figure 5 c , d ) (2, 36). The STE of Tetrahymena , distal stem-loop 4, inserts between the TRBD and the CTE (Figure 5 b – e ) (69, 70).…”

Section: The Catalytic Core Of Human and Tetrahymena Telomerasementioning

confidence: 99%

Progress in Human andTetrahymenaTelomerase Structure Determination

Chan

Wang²,

Feigon³

2017

Annu. Rev. Biophys.

View full text Add to dashboard Cite

Telomerase is an RNA–protein complex that extends the 3′ ends of linear chromosomes, using a unique telomerase reverse transcriptase (TERT) and template in the telomerase RNA (TR), thereby helping to maintain genome integrity. TR assembles with TERT and species-specific proteins, and telomerase function in vivo requires interaction with telomere-associated proteins. Over the past two decades, structures of domains of TR and TERT as well as other telomerase- and telomere-interacting proteins have provided insights into telomerase function. A recently reported 9-Å cryo–electron microscopy map of the Tetrahymena telomerase holoenzyme has provided a framework for understanding how TR, TERT, and other proteins from ciliate as well as vertebrate telomerase fit and function together as well as unexpected insight into telomerase interaction at telomeres. Here we review progress in understanding the structural basis of human and Tetrahymena telomerase activity, assembly, and interactions.

show abstract

The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA-DNA hybrids

Cited by 37 publications

References 32 publications

Structural conservation in the template/pseudoknot domain of vertebrate telomerase RNA from teleost fish to human

Structural conservation in the template/pseudoknot domain of vertebrate telomerase RNA from teleost fish to human

Fundamental mechanisms of telomerase action in yeasts and mammals: understanding telomeres and telomerase in cancer cells

Progress in Human andTetrahymenaTelomerase Structure Determination

Contact Info

Product

Resources

About