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Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation

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Roake, Caitlin M.
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Galati, Alessandra
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Bavasso, Francesca
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Micheli, Emanuela
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Saggio, Isabella
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Schoeftner, Stefan
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Cacchione, Stefano
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Gatti, Maurizio
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Artandi, Steven E.
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Genre
Journal article
Date
2020-02-04
Advisor
Committee member
Group
Lu Chen Lab (Temple University)
Fox Chase Cancer Center
Department
Cancer and Cellular Biology
Subject
TGS1
 hTR
 TERT
 Telomerase
 Telomeres
 Cap hypermethylation
 Telomere elongation
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http://hdl.handle.net/20.500.12613/9087
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ChenEtAl-JournalArticle-2020-02.pdf
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https://doi.org/10.1016/j.celrep.2020.01.004
Abstract
Biogenesis of the human telomerase RNA (hTR) involves a complex series of posttranscriptional modifications, including hypermethylation of the 5′ mono-methylguanosine cap to a tri-methylguanosine cap (TMG). How the TMG cap affects hTR maturation is unknown. Here, we show that depletion of trimethylguanosine synthase 1 (TGS1), the enzyme responsible for cap hypermethylation, increases levels of hTR and telomerase. Diminished trimethylation increases hTR association with the cap-binding complex (CBC) and with Sm chaperone proteins. Loss of TGS1 causes an increase in accumulation of mature hTR in both the nucleus and the cytoplasm compared with controls. In TGS1 mutant cells, increased hTR assembles with telomerase reverse transcriptase (TERT) protein to yield elevated active telomerase complexes and increased telomerase activity, resulting in telomere elongation in cultured human cells. Our results show that TGS1-mediated hypermethylation of the hTR cap inhibits hTR accumulation, restrains levels of assembled telomerase, and limits telomere elongation.
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Citation
Chen L, Roake CM, Galati A, Bavasso F, Micheli E, Saggio I, et al. Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation. Cell Rep. 2020 Feb 4;30(5):1358-1372.e5. doi:10.1016/j.celrep.2020.01.004.
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Cell Press
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Cell Reports, Vol. 30, Iss. 5
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