Emerging mechanisms of telomerase reactivation in cancer

Mutations in the promoter of human telomerase reverse transcriptase (hTERT) result in hyperactivation of hTERT. Notably, all mutations are G>A transitions, frequently found in a wide range of cancer types, and causally associated with cancer progression. Initially, the mutations were understood to reactivate hTERT by generating novel E26 transformation-specific (ETS) binding sites. Recent work reveals the role of DNA secondary structure G-quadruplexes, telomere binding factor(s), and chromatin looping in hTERT regulation. Here, we discuss these emerging findings in relation to the clinically significant promoter mutations to provide a broader understanding of the context-dependent outcomes that result in hTERT activation in normal and pathogenic conditions.