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

Robert J.A. Bell, H. Tomas Rube, Alex Kreig, Andrew Mancini, Shaun D. Fouse, Raman P. Nagarajan, Serah Choi, Chibo Hong, Daniel He, Melike Pekmezci, John K. Wiencke, Margaret R. Wrensch, Susan M. Chang, Kyle M. Walsh, Sua Myong, Jun S. Song, Joseph F. Costello

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1036-1039
Number of pages4
JournalScience
Volume348
Issue number6238
DOIs
StatePublished - May 29 2015

ASJC Scopus subject areas

  • General

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