Figure 4 (Key Figure). An expanded, C-strand-centric model for the evolution of the telomere protection and maintenance machinery based on potential kinship between CST and PT.

The following steps of telomere evolution are proposed. (i) In the proto-eukaryotic organism, the linearization of the genome by group II intron is initially accompanied by the D-loop mediated, BIR-like extension of the strand bearing the 3’ end. In addition, Pol α was enlisted from a virus to mediate C-strand synthesis, Concurrently, the archaeal-eukaryal RPA may have duplicated and given rise to the proto-CST complex (CST*) capable of regulating primase-Pol α. (ii) Subsequently, telomerase evolved from group II intron or a related reverse transcriptase to mediate the synthesis of short telomere repeats in cooperation with telomerase RNA. The proto-CST (CST*) has the necessary localization and DNA-binding property to also regulate telomerase at this stage of telomere evolution. (iii) Finally, the proto-CST underwent another round of duplication to give rise to PT–the proto-TEN1 was either not duplicated or lost during evolution. CST and PT underwent sub- and neofunctionalization such that PT acquired the ability to interact with other shelterin proteins and to specialize in the recruitment and activation of telomerase.