Tert promoter mutations increase sense and antisense transcription from the tert promoter

François Hafezi, Lisa Jaxel, Morgane Lemaire, Jonathan D. Turner, Danielle Perez-Bercoff*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Chief among mechanisms of telomerase reverse transcriptase (TERT) reactivation is the appearance of mutations in the TERT promoter. The two main TERT promoter mutations are C>T transitions located −146C>T and −124C>T upstream from the translational start site. They generate a novel Ets/TCF binding site. Both mutations are mutually exclusive and −124C>T is strikingly overrepresented in most cancers. We investigated whether this mutational bias and mutual exclusion could be due to transcriptional constraints. Methods: We compared sense and antisense transcription of a panel of TERT promoter-luciferase vectors harboring the −124C>T and −146C>T mutations alone or together. lncRNA TAPAS levels were measured by RT-PCR. Results: Both mutations generally increased TERT transcription by 2–4-fold regardless of upstream and downstream regulatory elements. The double mutant increased transcription in an additive fashion, arguing against a direct transcriptional constraint. The −146C>T mutation, alone or in combination with −124C>T, also unleashed antisense transcription. In line with this finding, lncRNA TAPAS was higher in cells with mutated TERT promoter (T98G and U87) than in cells with wild-type promoter, suggesting that lncRNA TAPAS may balance the effect of TERT promoter mutations. Conclusions: −146C>T and −124C>T TERT promoter mutations increase TERT sense and antisense transcription, and the double mutant features higher transcription levels. Increased antisense transcription may contain TERT expression within sustainable levels.

Original languageEnglish
Article number1773
JournalBiomedicines
Volume9
Issue number12
DOIs
Publication statusPublished - 26 Nov 2021

Keywords

  • Bidirectional promoter
  • LncRNA TAPAS
  • Telomerase
  • TERT
  • TERT promoter mutations
  • TERT transcription

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