<i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> Promoter
<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 upstr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/12/1773 |
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| author | François Hafezi Lisa Jaxel Morgane Lemaire Jonathan D. Turner Danielle Perez-Bercoff |
| author_facet | François Hafezi Lisa Jaxel Morgane Lemaire Jonathan D. Turner Danielle Perez-Bercoff |
| author_sort | François Hafezi |
| collection | DOAJ |
| description | <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. |
| first_indexed | 2024-03-10T04:33:21Z |
| format | Article |
| id | doaj.art-06c0cb4501c34e128463a45a124f3e4e |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T04:33:21Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-06c0cb4501c34e128463a45a124f3e4e2023-11-23T03:55:20ZengMDPI AGBiomedicines2227-90592021-11-01912177310.3390/biomedicines9121773<i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> PromoterFrançois Hafezi0Lisa Jaxel1Morgane Lemaire2Jonathan D. Turner3Danielle Perez-Bercoff4Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354 Esch-sur-Alzette, LuxembourgDepartment of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354 Esch-sur-Alzette, LuxembourgDepartment of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354 Esch-sur-Alzette, LuxembourgImmune Endocrine and Epigenetics Research Group, Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354 Esch-sur-Alzette, LuxembourgHIV Clinical and Translational Research Group, Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg<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.https://www.mdpi.com/2227-9059/9/12/1773<i>TERT</i> promoter mutationsTelomeraseTERT<i>TERT</i> transcriptionbidirectional promoterlncRNA <i>TAPAS</i> |
| spellingShingle | François Hafezi Lisa Jaxel Morgane Lemaire Jonathan D. Turner Danielle Perez-Bercoff <i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> Promoter Biomedicines <i>TERT</i> promoter mutations Telomerase TERT <i>TERT</i> transcription bidirectional promoter lncRNA <i>TAPAS</i> |
| title | <i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> Promoter |
| title_full | <i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> Promoter |
| title_fullStr | <i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> Promoter |
| title_full_unstemmed | <i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> Promoter |
| title_short | <i>TERT</i> Promoter Mutations Increase Sense and Antisense Transcription from the <i>TERT</i> Promoter |
| title_sort | i tert i promoter mutations increase sense and antisense transcription from the i tert i promoter |
| topic | <i>TERT</i> promoter mutations Telomerase TERT <i>TERT</i> transcription bidirectional promoter lncRNA <i>TAPAS</i> |
| url | https://www.mdpi.com/2227-9059/9/12/1773 |
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