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The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer

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Science  29 May 2015:
Vol. 348, Issue 6238, pp. 1036-1039
DOI: 10.1126/science.aab0015

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A mutant promoter's partner in crime

Telomerase is an enzyme that maintains the ends of chromosomes. TERT, the gene coding for the enzyme's catalytic subunit, is not expressed in healthy somatic cells, but its expression is reactivated in the majority of human cancers. The resultant high levels of telomerase help cancer cells survive and multiply. Recurrent mutations in the promoter region of TERT are associated with high telomerase levels in multiple cancer types. Bell et al. show that a specific transcription factor called GABP is selectively recruited to the mutant form of the TERT promoter, which activates TERT gene expression

Science, this issue p. 1036

Abstract

Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.

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