Human Replication Protein A complex is a Telomerase Processivity Factor Essential for Telomere Maintenance
Agrawal, S.; Lin, X.; Susvirkar, V.; O'Connor, M. S.; Chavez, B. L.; Tholkes, V. R.; Abe, K. M.; He, Q.; Huang, X.; Lim, C. J.
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Telomerase is crucial for maintaining telomere length and safeguarding genome stability. In this study, we identified Replication Protein A (RPA) as a novel telomerase processivity factor, functioning alongside the telomerase recruitment factor TPP1-POT1. AlphaFold2 predictions revealed that RPA and TPP1 interact with telomerase at distinct binding sites. Using separation- of-function mutants, we discovered that RPA-mediated telomerase stimulation is indispensable for telomere elongation, while TPP1-POT1 primarily functions in recruiting telomerase to telomeres. Furthermore, we demonstrated that short telomere disease-associated telomerase mutations compromise RPAs ability to stimulate telomerase, establishing a link between impaired RPA-dependent processivity and telomeropathies. Our findings redefine human telomerase regulation by establishing RPA as a critical regulator and provide new insights into the molecular basis of telomere-related diseases.
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