Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres

Human shelterin components POT1 and TPP1 form a stable heterodimer that protects telomere ends from ATR-dependent DNA damage responses and regulates telomerase-dependent telomere extension. Mice possess two functionally distinct POT1 proteins. POT1a represses ATR/CHK1 DNA damage responses and the alternative non-homologous end-joining DNA repair pathway while POT1b regulates C-strand resection and recruits the CTC1-STN1-TEN1 (CST) complex to telomeres to mediate C-strand fill-in synthesis. Whether POT1a and POT1b are involved in regulating the length of the telomeric G-strand is unclear. Here we demonstrate that POT1b, independent of its CST function, enhances recruitment of telomerase to telomeres through three amino acids in its TPP1 interacting C-terminus. POT1b thus coordinates the synthesis of both telomeric G- and C-strands. In contrast, POT1a negatively regulates telomere length by inhibiting telomerase recruitment to telomeres. The identification of unique amino acids between POT1a and POT1b helps us understand mechanistically how human POT1 switches between end protective functions and promoting telomerase recruitment. Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects telomere ends. The authors exploit the observation that mice have two POT1 paralogs, enabling functional dissections to shed important light on the mechanistic basis for human POT1 functions.

Automated summary

The human shelterin proteins POT1 and TPP1 form a stable heterodimer that protects telomere ends. Two functionally distinct POT1 proteins in mice have been identified, with POT1b enhancing telomerase recruitment to telomeres and coordinating the synthesis of telomeric G- and C-strands, while POT1a negatively regulates telomere length by inhibiting telomerase recruitment. The discovery of unique amino acids between POT1a and POT1b sheds light on the mechanistic basis for their different functions in regulating telomeres.