It all comes together at the ends: Telomerase structure, function, and biogenesis

Podlevsky, Joshua D.; Chen, Julian J.‐L.

doi:10.1016/j.mrfmmm.2011.11.002

Cited by 124 publications

(115 citation statements)

References 143 publications

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“…TERT belongs to the reverse transcriptase (RT) family and contains an RT domain with all RT-specific motifs (1, 2, and A-E motifs) [15]. Unlike classical RTs, telomerase requires an obligatory internal RNA component as a template for DNA synthesis and can copy the template sequence repetitively through efficient translocation.…”

Section: Introductionmentioning

confidence: 99%

A trans-spliced telomerase RNA dictates telomere synthesis in Trypanosoma brucei

et al. 2013

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Telomerase is a ribonucleoprotein enzyme typically required for sustained cell proliferation. Although both telomerase activity and the telomerase catalytic protein component, TbTERT, have been identified in the eukaryotic pathogen Trypanosoma brucei, the RNA molecule that dictates telomere synthesis remains unknown. Here, we identify the RNA component of Trypanosoma brucei telomerase, TbTR, and provide phylogenetic and in vivo evidence for TbTR's native folding and activity. We show that TbTR is processed through trans-splicing, and is a capped transcript that interacts and copurifies with TbTERT in vivo. Deletion of TbTR caused progressive shortening of telomeres at a rate of 3-5 bp/population doubling (PD), which can be rescued by ectopic expression of a wild-type allele of TbTR in an apparent dose-dependent manner. Remarkably, introduction of mutations in the TbTR template domain resulted in corresponding mutant telomere sequences, demonstrating that telomere synthesis in T. brucei is dependent on TbTR. We also propose a secondary structure model for TbTR based on phylogenetic analysis and chemical probing experiments, thus defining TbTR domains that may have important functional implications in telomere synthesis. Identification and characterization of TbTR not only provide important insights into T. brucei telomere functions, which have been shown to play important roles in T. brucei pathogenesis, but also offer T. brucei as an attractive model system for studying telomerase biology in pathogenic protozoa and for comparative analysis of telomerase function with higher eukaryotes.

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Section: Introductionmentioning

confidence: 99%

A trans-spliced telomerase RNA dictates telomere synthesis in Trypanosoma brucei

et al. 2013

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“…4,5 The telomerase holoenzyme is an RNP, which has an noncoding RNA component called telomerase RNA (TER), a specialized telomerase reverse transcriptase (TERT) and several species-specific accessory proteins. 5,6 The accessory proteins are involved in regulation of holoenzyme biogenesis, assembly, localization and activity in vivo. 7 TER provides a template for telomere repeat synthesis by TERT and also acts as a scaffold on which the telomerase proteins assemble (Fig.…”

Section: Introductionmentioning

confidence: 99%

xRRM

Singh¹,

Choi

Feigon³

2013

RNA Biology

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Genuine La and La-related proteins group 7 (LARP7) bind to the non-coding RNAs transcribed by RNA polymerase III (RNAPIII), which end in UUU-3'OH. The La motif and RRM1 of these proteins (the La module) cooperate to bind the UUU-3'OH, protecting the RNA from degradation, while other domains may be important for RNA folding or other functions. Among the RNAPIII transcripts is ciliate telomerase RNA (TER). p65, a member of the LARP7 family, is an integral Tetrahymena thermophila telomerase holoenzyme protein required for TER biogenesis and telomerase RNP assembly. p65, together with TER and telomerase reverse transcriptase (TERT), form the Tetrahymena telomerase RNP catalytic core. p65 has an N-terminal domain followed by a La module and a C-terminal domain, which binds to the TER stem 4. We recently showed that the p65 C-terminal domain harbors a cryptic, atypical RRM, which uses a unique mode of single-and doublestrand RNA binding and is required for telomerase RNP catalytic core assembly. This domain, which we named xRRM, appears to be present in and unique to genuine La and LARP7 proteins. Here we review the structure of the xRRM, discuss how this domain could recognize diverse substrates of La and LARP7 proteins and discuss the functional implications of the xRRM as an RNP chaperone.

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“…Telomerase catalytic activity can be reconstituted by the combination of hTR and hTERT in a eukaryotic cell or cell extract (5,6). In addition to these two RNP catalytic core subunits, many additional proteins are necessary for the in vivo assembly, subcellular trafficking, and telomere association of a functional telomerase holoenzyme (7,8).…”

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confidence: 99%

Dynamics of Human Telomerase Holoenzyme Assembly and Subunit Exchange across the Cell Cycle

Vogan

Collins

2015

Journal of Biological Chemistry

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Background: Telomerase elongation of chromosome ends is restricted within the cell cycle. Results: A human telomerase holoenzyme subunit mediating Cajal body and telomere localization disassembles reversibly from the RNP catalytic core in each cell cycle. Conclusion: Telomerase holoenzyme assembly and disassembly are favored at distinct stages of the cell cycle. Significance: Human telomerase is relicensed for telomere synthesis in G 1 .

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It all comes together at the ends: Telomerase structure, function, and biogenesis

Cited by 124 publications

References 143 publications

A trans-spliced telomerase RNA dictates telomere synthesis in Trypanosoma brucei

A trans-spliced telomerase RNA dictates telomere synthesis in Trypanosoma brucei

xRRM

Dynamics of Human Telomerase Holoenzyme Assembly and Subunit Exchange across the Cell Cycle

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