Alternative splicing is a developmental switch for hTERT expression

Penev, Alex; Bazley, Andrew; Shen, Michael; Boeke, Jef D.; Savage, Sharon A.; Sfeir, Agnel

doi:10.1016/j.molcel.2021.03.033

Cited by 22 publications

(4 citation statements)

References 73 publications

(117 reference statements)

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“…The most studied hTERT splice variants are minus-alpha, beta, gamma and delta4-13, which affect the reverse transcriptase domain (RT) encoded by exons 5-9, inhibit enzymatic activity and result in impaired telomere maintenance. All variants capable of binding the telomerase RNA component (TERC) are commonly considered as dominant-negative isoforms involved in post-transcriptional regulation of hTERT (Colgin et al, 2000;Yi et al, 2000Yi et al, , 2001Penev et al, 2021). Another isoform identified in vertebrates and likely involved in post-transcriptional regulation is the DEL2 lacking the second exon.…”

Section: Discussionmentioning

confidence: 99%

Extended longevity of termite kings and queens is accompanied by extranuclear localization of telomerase in somatic organs and caste-specific expression of its isoforms

Pangrácová,

Křivánek,

Vrchotová

et al. 2024

Preprint

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Kings and queens of termites are endowed with an extraordinary longevity coupled with lifelong fecundity. We recently reported that termite kings and queens display a dramatically increased enzymatic activity and abundance of telomerase in their somatic organs when compared to short-lived workers and soldiers. We hypothesized that this telomerase activation may represent a non-canonical pro-longevity function, independent of its canonical role in telomere maintenance. Here, we explore this avenue and investigate whether the presumed non-canonical role of telomerase may be due to alternative splicing of the catalytic telomerase subunit TERT and whether the subcellular localization of TERT isoforms differs among organs and castes in the termite Prorhinotermes simplex. We empirically confirm the expression of four in silico predicted splice variants (psTERT1-A, psTERT1-B, psTERT2-A, psTERT2-B), defined by N-terminal splicing implicating differential localizations, and C-terminal splicing giving rise to full-length and truncated isoforms. We show that the transcript proportions of the psTERT are caste- and tissue-specific and that the extranuclear full-length isoform TERT1-A is relatively enriched in the soma of neotenic kings and queens compared to their gonads and to the soma of workers. We also show that extranuclear TERT protein quantities are significantly higher in the soma of kings and queens compared to workers, namely due to the cytosolic TERT. Independently, we confirm by microscopy the extranuclear TERT localization in somatic organs. We conclude that the presumed pleiotropic action of telomerase combining the canonical nuclear role in telomere maintenance with extranuclear functions is driven by complex TERT splicing.

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Section: Discussionmentioning

confidence: 99%

Extended longevity of termite kings and queens is accompanied by extranuclear localization of telomerase in somatic organs and caste-specific expression of its isoforms

Pangrácová,

Křivánek,

Vrchotová

et al. 2024

Preprint

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“…TAPAS depletion and over-expression in cancer cells led to significantly enhanced and diminished TERT expression, respectively ( 78 , 79 ). In addition, the nuclear accumulation of TERT mRNA occurs frequently in cancer cells, and intron retention is identified as a underlying mechanism ( 80 , 81 ). TAPAS was similarly observed to induce accumulation of TERT mRNA in nucleus, and such effect prevented access of TERT transcripts to the translational machinery, thereby inhibiting TERT protein translation ( 79 ).…”

Section: The Tert Promoter Methylation and Cooperation With Tert Prom...mentioning

confidence: 99%

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

Liu

Xia

et al. 2023

Front. Immunol.

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Telomerase, an RNA-dependent DNA polymerase synthesizing telomeric TTAGGG sequences, is primarily silent in normal human urothelial cells (NHUCs), but widely activated in urothelial cell-derived carcinomas or urothelial carcinomas (UCs) including UC of the bladder (UCB) and upper track UC (UTUC). Telomerase activation for telomere maintenance is required for the UC development and progression, and the key underlying mechanism is the transcriptional de-repression of the telomerase reverse transcriptase (TERT), a gene encoding the rate-limiting, telomerase catalytic component. Recent mechanistic explorations have revealed important roles for TERT promoter mutations and aberrant methylation in activation of TERT transcription and telomerase in UCs. Moreover, these TERT-featured genomic and epigenetic alterations have been evaluated for their usefulness in non-invasive UC diagnostics, recurrence monitoring, outcome prediction and response to treatments such as immunotherapy. Importantly, the detection of the mutated TERT promoter and TERT mRNA as urinary biomarkers holds great promise for urine-based UC liquid biopsy. In the present article, we review recent mechanistic insights into altered TERT promoter-mediated telomerase activation in UCs and discuss potential clinical implications. Specifically, we compare differences in senescence and transformation between NHUCs and other types of epithelial cells, address the interaction between TERT promoter mutations and other factors to affect UC progression and outcomes, evaluate the impact of TERT promoter mutations and TERT-mediated activation of human endogenous retrovirus genes on UC immunotherapy including Bacillus Calmette-Guérin therapy and immune checkpoint inhibitors. Finally, we suggest the standardization of a TERT assay and evaluation system for UC clinical practice.

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“…Telomerase levels are down-regulated in most human cells at some point during in utero growth and differentiation to limit the number of subsequent cell divisions. Both alternative splicing and transcriptional regulation of the telomerase transcriptase gene ( hTERT ) have been implicated in the silencing of telomerase activity ( 8 , 74 ). However, details of the timing and degree of telomerase silencing during development and differences between specific cell types remain to be clarified.…”

Section: Telomere Regulation In Uteromentioning

confidence: 99%

Telomere Length Regulation

Lansdorp

2022

Front. Oncol.

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The number of (TTAGGG)n repeats at the ends of chromosomes is highly variable between individual chromosomes, between different cells and between species. Progressive loss of telomere repeats limits the proliferation of pre-malignant human cells but also contributes to aging by inducing apoptosis and senescence in normal cells. Despite enormous progress in understanding distinct pathways that result in loss and gain of telomeric DNA in different cell types, many questions remain. Further studies are needed to delineate the role of damage to telomeric DNA, replication errors, chromatin structure, liquid-liquid phase transition, telomeric transcripts (TERRA) and secondary DNA structures such as guanine quadruplex structures, R-loops and T-loops in inducing gains and losses of telomere repeats in different cell types. Limitations of current telomere length measurements techniques and differences in telomere biology between species and different cell types complicate generalizations about the role of telomeres in aging and cancer. Here some of the factors regulating the telomere length in embryonic and adult cells in mammals are discussed from a mechanistic and evolutionary perspective.

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Alternative splicing is a developmental switch for hTERT expression

Cited by 22 publications

References 73 publications

Extended longevity of termite kings and queens is accompanied by extranuclear localization of telomerase in somatic organs and caste-specific expression of its isoforms

Extended longevity of termite kings and queens is accompanied by extranuclear localization of telomerase in somatic organs and caste-specific expression of its isoforms

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

Telomere Length Regulation

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