(A) An overview of human telomerase catalytic core. Left panel, the structure of the catalytic core. Proteins are shown in surface representation, and nucleic acids are shown in cartoon representation. Right panel, a cartoon schematic of telomerase catalytic core. Colour schemes are shown in Figure 1A,B are used for hTERT and hTR domains. (B) Interaction of the CR4/5 domain of hTR with the TRBD and CTE domains of hTERT and histone H2A–H2B. (C) Left panel, close-up view of the substrate-template duplex held in the active site by the palm, fingers and thumb polymerase sub-domains of hTERT. Right panel, a cartoon schematic of the left panel. The RT domain of hTERT harbours the palm and fingers sub-domains while CTE domain is also known as the thumb. The catalytic triad (D712, D868 and D869) are indicated. The vacant nucleotide-binding site is also indicated with an asterisk. (D) DNA substrate recognition by the TRBD, RT and CTE domains of hTERT. Specific side-chain interactions are also highlighted. The vacant nucleotide-binding site is indicated with an asterisk. (E) A simplified model of the repeat addition processivity catalytic cycle of human telomerase. The cycle consists of four main steps: alignment, elongation, termination and translocation. The structure shown in (A,B) captured the complex in an elongation state as indicated by the asterisk. The base-pairing lines drawn for the alignment and termination steps are hypothetical.