fig1

Figure 1. Proposed model for telomerase reactivation by telomerase reverse transcriptase (TERT) promoter mutations. The C228T and C250T TERT promoter mutation both create an E-twenty-six (ETS) binding motif (the mutational hotspots are in red) to modulate TERT mRNA expression. P52 (NF-κB2) is recruited to the C250T region, but not the C228T region, and cooperates with ETS factors to drive efficient TERT transcription. The elevated TERT expression enhances cell malignant behavior through a telomere lengthening-dependent manner (maintaining telomere length or inhibiting senescence), and/or a telomere lengthening-independent manner (TERT acting as a transcriptional modulator regulating genes related to Wnt and NF-κB signaling pathways thereby promoting cell proliferation, antiapoptosis, and stem cell renewal). Hepatitis B virus (HBV) DNA insertion into TERT promoter is another possible mechanism of hepatocarcinogenesis, which may cause HBV promoter/enhancer-driven transcription of TERT