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

Lu Chen, Caitlin M. Roake, Alessandra Galati, Francesca Bavasso, Emanuela Micheli, Isabella Saggio, Stefan Schoeftner, Stefano Cacchione, Maurizio Gatti, Steven E. Artandi, Grazia D. Raffa

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish
Pages (from-to)1358-1372.e5
JournalCell Reports
Volume30
Issue number5
DOIs
StatePublished - Feb 4 2020

Keywords

  • Biocatalysis
  • Coiled Bodies/metabolism
  • Guanosine/metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Methylation
  • Methyltransferases/deficiency
  • Models, Biological
  • Mutation/genetics
  • Polyadenylation
  • RNA Caps/metabolism
  • RNA/metabolism
  • Subcellular Fractions/metabolism
  • Telomerase/metabolism
  • Telomere/metabolism

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