Human RPA is an essential telomerase processivity factor for maintaining telomeres
- Sourav Agrawal
- Xiuhua Lin
- Vivek Susvirkar
- Michael S. O’Connor
- Bianca L. Chavez
- Victoria R. Tholkes
- Grace P. Tauber
- Qixiang He
- Kaitlyn M. Abe
- Xuhui Huang
- Ci Ji Lim
2025-10-30
Telomerase counteracts telomere shortening by repeatedly adding DNA repeats to chromosome ends. We identified the replication protein A (RPA) heterotrimer as a telomerase processivity factor critical for telomere maintenance. RPA stimulates telomerase processivity in vitro, and AlphaFold modeling predicts that RPA engages a telomerase surface distinct from the one bound by the shelterin subunit TPP1. Guided by these predictions, we engineered separation-of-function telomerase reverse transcriptase (TERT) mutants and found that the loss of RPA-mediated stimulation impairs telomere elongation, even when TPP1–POT1–mediated stimulation remains intact. Furthermore, short-telomere disease–associated TERT mutations reduce RPA-dependent telomerase stimulation, revealing a mechanistic link between impaired processivity and telomeropathies. Together, our findings establish human RPA as a key regulator of telomerase and offer molecular insights into telomere-related disease mechanisms.