E4F1 and ZNF148 are transcriptional activators of the A57C and wildtype TERT promoter

ABSTRACT: Point mutations within the TERT promoter are the most common recurrent somatic non-coding mutation identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma and bladder cancer. They are most abundant at C146T and C124T and more rare at A57C, with the latter originally described as a familial case but subsequently shown also to occur somatically. All three mutations create de novo ETS (E-twenty-six specific) binding sites and result in the reactivation of the TERT gene, allowing cancer cells to achieve replicative immortality. Here, we employed a systematic proteomics screen to identify transcription factors preferentially binding to the C146T, C124T and A57C mutations. While we confirmed binding of multiple ETS factors to the mutant C146T and C124T sequences, we identified E4F1 a an A57C-specific binder and ZNF148 as a TERT WT binder that is excluded from the TERT promoter by the C124T allele. Both proteins are activating transcription factors that bind specifically to the A57C and wildtype (at position 124) TERT promoter sequence in corresponding cell lines and upregulate TERT transcription and telomerase activity.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Cancer

SUBMITTER: Dennis Kappei  

LAB HEAD: Dennis Kappei

PROVIDER: PXD037776 | Pride | 2023-11-04

REPOSITORIES: Pride