AUTHOR=Tornesello Maria Lina , Cerasuolo Andrea , Starita Noemy , Amiranda Sara , Bonelli Patrizia , Tuccillo Franca Maria , Buonaguro Franco M. , Buonaguro Luigi , Tornesello Anna Lucia 

TITLE=Reactivation of telomerase reverse transcriptase expression in cancer: the role of TERT promoter mutations

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 11 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1286683

DOI=10.3389/fcell.2023.1286683

ISSN=2296-634X

ABSTRACT=Telomerase activity and telomere elongation are essential conditions for the unlimited proliferation of neoplastic cells. Point mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been found to occur at high frequencies in several tumour types and considered a primary cause of telomerase reactivation in cancer cells.These mutations promote TERT gene expression by multiple mechanisms, including the generation of novel binding sites for nuclear transcription factors, displacement of negative regulators from DNA G-quadruplexes, recruitment of epigenetic activators and disruption of longrange interactions between TERT locus and telomeres. Furthermore, TERT promoter mutations cooperate with TPP1 promoter nucleotide changes to lengthen telomeres and with mutated BRAF and FGFR3 oncoproteins to enhance oncogenic signalling in cancer cells.TERT promoter mutations have been recognized as an early marker of tumour development or a major indicator of poor outcome and reduced patients survival in several cancer types. In this review, we summarize recent findings on the role of TERT promoter mutations, telomerase expression and telomeres elongation in cancer development, their clinical significance and therapeutic opportunities.The discovery of hot spot mutations in the core promoter region of TERT gene emerged as the most important event for the telomerase reverse transcriptase (TERT) reactivation in numerous cancer types. These mutations generate de novo binding sites for E-twenty-six (ETS) transcription factors, particularly the GABP heterotetramer complex that selectively binds and activates the mutant TERT promoter. The increasing number of genomic studies has generated important results showing the synergistic interaction between TERT promoter mutations and other oncogenic variations. Furthermore, analysis of the three-dimensional organization of genomes revealed complex linkages between telomeric factors and mutant TERT promoter that shed light on new mechanisms of restoration of telomerase activity during tumorigenesis.