Alternative splicing regulation of telomerase: a new paradigm?

Wong, Mandy S.; Wright, Woodring E.; Shay, Jerry W.

doi:10.1016/j.tig.2014.07.006

Cited by 86 publications

(76 citation statements)

References 77 publications

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“…However, while we observed increased transcription of exon 1 of h TERT , there must be additional mechanisms preventing the inclusion of exons critical to produce active telomerase. There is substantial evidence that alternative splicing of h TERT may also have a major role in suppressing the production of active telomerase in old cells [22–24]. Furthermore, we performed 3D-FISH analysis in transformed SW26 and SW39 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Cells with long telomeres at the end of chromosome 5p in young passaged cells form a chromatin loop in the region of the h TERT locus. Importantly, we demonstrated that the chromatin loop is disengaged in cells with short telomeres, leading to partial increased expression of h TERT mRNA during in vitro aging and in response to p21 knockdown; however, telomerase activity was not detected, and, alternatively, spliced variants were likely produced [17,22–24,38]. Finally, we demonstrated that, in old cells with short telomeres, re-introduction of h TERT and elongation of telomeres results in a re-engagement of TPE-OLD.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer

et al. 2016

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Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer

et al. 2016

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“…Intrinsic to the model is the long-held notion that telomeres undergo progressive erosion during the clonal expansion until telomerase is activated by mechanisms that might include telomerase reverse transcriptase gene (TERT) promoter mutations, transcriptional changes, epigenetic/chromatin modifications and splicing alterations [39]. Thus, telomerase activation during clonal expansion is permissive to the development of most cancers, as recently illustrated for the accumulating mutations in expanding nevi while they undergo successive stages of transformation into malignant melanoma [3].…”

Section: The Potential Resolution Of the Cancer-telomere Length Paradoxmentioning

confidence: 99%

Mutations, Cancer and the Telomere Length Paradox

2017

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Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability— a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely telomere length-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.

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“…The current accurate estimate for the quantity of catalytically active telomerase molecules is 50–100 per cell [42], produced from approximately 20 mRNA molecules per cell. The minority of the hTERT transcripts were spliced into the full-length isoform with telomerase activity [43]. A working explanation of these results was that the transcriptional machinery was not able to reduce the transcription to a level that produces only a few mRNA molecules within a single cell.…”

Section: Htert Pre-mrna Alternative Splicing Regulation In Cancer mentioning

confidence: 99%

Alternative Splicing of hTERT Pre-mRNA: A Potential Strategy for the Regulation of Telomerase Activity

Wang

Chang

et al. 2017

IJMS

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The activation of telomerase is one of the key events in the malignant transition of cells, and the expression of human telomerase reverse transcriptase (hTERT) is indispensable in the process of activating telomerase. The pre-mRNA alternative splicing of hTERT at the post-transcriptional level is one of the mechanisms for the regulation of telomerase activity. Shifts in splicing patterns occur in the development, tumorigenesis, and response to diverse stimuli in a tissue-specific and cell type–specific manner. Despite the regulation of telomerase activity, the alternative splicing of hTERT pre-mRNA may play a role in other cellular functions. Modulating the mode of hTERT pre-mRNA splicing is providing a new precept of therapy for cancer and aging-related diseases. This review focuses on the patterns of hTERT pre-mRNA alternative splicing and their biological functions, describes the potential association between the alternative splicing of hTERT pre-mRNA and telomerase activity, and discusses the possible significance of the alternative splicing of the hTERT pre-mRNA in the diagnosis, therapy, and prognosis of cancer and aging-related diseases.

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Alternative splicing regulation of telomerase: a new paradigm?

Cited by 86 publications

References 77 publications

Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer

Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer

Mutations, Cancer and the Telomere Length Paradox

Alternative Splicing of hTERT Pre-mRNA: A Potential Strategy for the Regulation of Telomerase Activity

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