title: Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers.
abstract: Somatic mutations in the promoter of the gene for telomerase reverse transcriptase (TERT) are the most common noncoding mutations in cancer. They are thought to activate telomerase, contributing to proliferative immortality, but the molecular events driving TERT activation are largely unknown. We observed in multiple cancer cell lines that mutant TERT promoters exhibit the H3K4me2/3 mark of active chromatin and recruit the GABPA/B1 transcription factor, while the wild-type allele retains the H3K27me3 mark of epigenetic silencing; only the mutant promoters are transcriptionally active. These results suggest how a single-base-pair mutation can cause a dramatic epigenetic switch and monoallelic expression.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA; Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, Colorado 80309, USA;
authors.forename: Josh Lewis
authors.initials: JL
authors.lastname: Stern
authors.affiliation: University of Colorado Comprehensive Cancer Center, Aurora, Colorado 80045, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA; Department of Surgery (Urology), University of Colorado, Aurora, Colorado 80045, USA;
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231, USA.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA; Howard Hughes Medical Institute, University of Colorado BioFrontiers Institute, Boulder, Colorado 80309, USA; University of Colorado Comprehensive Cancer Center, Aurora, Colorado 80045, USA;
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cech
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D019098:Telomerase / Q000235:genetics*
chemical_list: D002843:Chromatin; D051268:GA-Binding Protein Transcription Factor; C495661:GABPA protein, human; C495662:GABPB1 protein, human; D019098:Telomerase
keywords: TERT; chromatin; monoallelic; noncoding mutations; promoter; telomerase