期刊
SCIENCE
卷 348, 期 6238, 页码 1036-1039出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aab0015
关键词
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资金
- National Cancer Institute (NCI) [R01CA163336]
- Sontag Foundation Distinguished Scientist Award
- NCI [P50CA097257, P01CA118816-06, R01CA169316-01, R25CA112355, R01CA52689]
- Grove Foundation
- Karen Osney Brownstein Endowed Chair
- Anne and Jason Farber Foundation
- Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research
- Robert Magnin Newman Endowed Chair in Neuro-oncology
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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