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bioRxiv · 10.1101/2024.08.16.608355

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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Abstract

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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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.. 2024-08-17. Human Replication Protein A complex is a Telomerase Processivity Factor Essential for Telomere Maintenance. https://doi.org/10.1101/2024.08.16.608355

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