Figure 3.

Extratelomeric functions of TERT. In the nucleus (left), TERT carries out its canonical role in telomere extension in complex with the other components of the telomerase holoenzyme (TR, dyskerin, GAR1, NOP10, NHP2). In addition, TERT binds to the promoters of genes that encode key growth factors (EGF, VEGF), as well as secondary effectors of tumor-promoting signaling pathways (Wnt, NF-κB, TGF-β), thereby positively or negatively regulating their expression. These transcriptional effects are frequently mediated by the actions of TFs or chromatin remodelers (CR) that complex with TERT at its target loci and influence both local and distant chromatin structure (i.e., at enhancers). In mitochondria (right), TERT possesses transcriptional, metabolic, and detoxification functions. In particular, TERT recognizes specific sites in the mitochondrial genome (mtDNA), which both alters mitochondrial gene expression and shields mtDNA from damage. Additionally, TERT plays a DNA-independent role in the neutralization of reactive oxygen species (ROS), which otherwise induces DNA damage and institute a host of aberrations in cellular metabolism and survival.