| Summary: | <b>Background:</b> Chief among mechanisms of telomerase reverse transcriptase (TERT) reactivation is the appearance of mutations in the <i>TERT</i> promoter. The two main <i>TERT</i> 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. <b>Methods:</b> We compared sense and antisense transcription of a panel of <i>TERT</i> promoter-<i>luciferase</i> vectors harboring the −124C>T and -146C>T mutations alone or together. lncRNA <i>TAPAS</i> levels were measured by RT-PCR. <b>Results:</b> Both mutations generally increased <i>TERT</i> 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 <i>TAPAS</i> was higher in cells with mutated <i>TERT</i> promoter (T98G and U87) than in cells with wild-type promoter, suggesting that lncRNA <i>TAPAS</i> may balance the effect of <i>TERT</i> promoter mutations. <b>Conclusions</b>: −146C>T and −124C>T <i>TERT</i> promoter mutations increase <i>TERT</i> sense and antisense transcription, and the double mutant features higher transcription levels. Increased antisense transcription may contain <i>TERT</i> expression within sustainable levels.
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