Replication Protein A Found to Support Telomere Regulation by Stimulating Telomerase

Recent research from the University of Wisconsin–Madison details a critical role of replication protein A (RPA) in the regulation of telomere length by stimulating telomerase enzyme activity. Telomeres, protective caps at chromosome ends composed of repetitive DNA and proteins, maintain genome stability by preventing DNA degradation and unwanted recombination. While shortening of telomeres occurs naturally with aging, insufficient maintenance leads to chromosomal instability and diseases such as aplastic anemia, myelodysplastic syndrome, and certain leukemias.

The research team used AlphaFold to identify interactions between telomerase and other proteins, discovering that RPA acts as an essential telomerase processivity factor in humans. Whereas RPA’s known functions include DNA replication and repair, this study experimentally confirmed its necessity for stimulating telomerase to elongate telomeres effectively. The study showed that mutations impairing RPA’s ability to facilitate telomerase are linked to telomere-related diseases, providing explanations for cases unresolved by previous knowledge.

These insights connect RPA dysfunction to clinical disorders involving shortened telomeres, clarifying disease mechanisms and enabling new diagnostic avenues. “There are some patients with shortened telomere disorders that couldn't be explained with our previous body of knowledge, explains Ci Ji Lim, first author of the paper published in Science. “Now we have an answer to the underlying cause of some of these short telomere disease mutations: it is a result of RPA not being able to stimulate telomerase.” This molecular understanding allows clinicians to test patients’ mutations for impacts on the RPA-telomerase interaction, offering meaningful explanations and guiding further investigation.

The findings underscore that telomere regulation depends on the coordinated action of telomerase and accessory factors like RPA to maintain chromosome stability and genome integrity. Such regulation is critical to cellular health, and disruptions may lead to premature aging and cancer.