TY - JOUR
T1 - Tert promoter mutations increase sense and antisense transcription from the tert promoter
AU - Hafezi, François
AU - Jaxel, Lisa
AU - Lemaire, Morgane
AU - Turner, Jonathan D.
AU - Perez-Bercoff, Danielle
N1 - Funding Information:
Funding: This work was supported by the Ministère de l’Education et de la Recherche du Luxembourg; FH is supported by the Fonds National de la Recherche du Luxembourg FNR-PRIDE scheme (PRIDE/11012546/NEXTIMMUNE).
Funding Information:
This work was supported by the Minist?re de l?Education et de la Recherche du Luxem-bourg; FH is supported by the Fonds National de la Recherche du Luxembourg FNR-PRIDE scheme (PRIDE/11012546/NEXTIMMUNE).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/11/26
Y1 - 2021/11/26
N2 - 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.
AB - 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.
KW - Bidirectional promoter
KW - LncRNA TAPAS
KW - Telomerase
KW - TERT
KW - TERT promoter mutations
KW - TERT transcription
UR - http://www.scopus.com/inward/record.url?scp=85120578301&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/34944589
U2 - 10.3390/biomedicines9121773
DO - 10.3390/biomedicines9121773
M3 - Article
C2 - 34944589
AN - SCOPUS:85120578301
SN - 2227-9059
VL - 9
JO - Biomedicines
JF - Biomedicines
IS - 12
M1 - 1773
ER -