Activating mutations in the Telomerase Reverse Transcriptase (TERT) promoter are the single most common non-coding mutation in cancer and enable limitless cell division characteristic of immortal cells1-12. Solving the immortality mechanism represents a major step towards selectively reversing it in cancer cells. TERT promoter mutations create a de novo E26 transformation specific (ETS) transcription factor binding motif, however most of the 28 ETS factors and many other transcriptional regulators have been implicated13-22. Cancer type and mutation specific mechanisms have also been proposed. Here, we uniformly and robustly analyzed fifty-three cell lines representing sixteen cancer types and six recurrent mutations and found that a tetramer of the GA-binding protein (GABP) is specifically responsible for mutant TERT promoter activation in all cases, with no such role in TERT promoter wild type cells. Strikingly, TERT expression is maintained in tetramer depleted tumor cells. We show how and why the tetramer is serially replaced, not by other transcription factors, but by GABP dimers and then weakly by a paralogous tetramer complex. Elimination of the tetramer and dimer reinstates epigenetic repression of TERT, activates checkpoint programs and prevents cancer cell division. We conclude that unique features of the GABP tetramer must therefore determine positive selection of nearly all TERT promoter mutations in human cancer. Furthermore, domains shared among the three GABP complexes present pan-cancer vulnerabilities.