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

RJA Bell, HT Rube, A Kreig, A Mancini, SD Fouse… - Science, 2015 - science.org
RJA Bell, HT Rube, A Kreig, A Mancini, SD Fouse, RP Nagarajan, S Choi, C Hong, D He…
Science, 2015science.org
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 …
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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