Researchers at the University of Wisconsin–Madison have shown that the protein replication protein A (RPA) is essential for telomerase activity that helps maintain long, healthy telomeres. The work, reported in the journal Science, sheds light on previously unexplained cases of short telomere disorders and may open new diagnostic avenues for patients with conditions such as aplastic anemia and certain leukemias.
Telomeres, the protective caps at the ends of chromosomes, naturally shorten as cells divide. When telomeres erode too quickly, the resulting genomic instability can accelerate aging and contribute to serious disease.
A team working in the laboratory of Ci Ji Lim, a professor of biochemistry at the University of Wisconsin–Madison, set out to identify proteins that partner with telomerase, the enzyme that maintains telomere length. Malfunctions in such partner proteins are believed to underlie some disorders caused by shortened telomeres.
According to a summary from the University of Wisconsin–Madison, graduate student Sourav Agrawal, research scientist Xiuhua Lin, and postdoctoral researcher Vivek Susvirkar led the search for proteins likely to interact with telomerase. Using AlphaFold, an artificial intelligence tool that predicts three‑dimensional protein structures and protein–protein interactions, they pinpointed replication protein A (RPA). Previously known for its roles in DNA replication and repair, RPA had not been confirmed as a critical factor in human telomere maintenance.
Guided by AlphaFold predictions, the researchers experimentally verified that, in humans, RPA is required to stimulate telomerase and support the maintenance of telomere length. The Science paper describes RPA as an essential telomerase processivity factor, meaning it helps the enzyme repeatedly add DNA repeats to chromosome ends.
"This line of research goes beyond a biochemical understanding of a molecular process. It deepens clinical understanding of telomere diseases," Lim said, in comments released by the university. The findings have direct relevance for patients with life‑threatening illnesses linked to short telomeres, including aplastic anemia, myelodysplastic syndrome and acute myeloid leukemia.
"There are some patients with shortened telomere disorders that couldn't be explained with our previous body of knowledge," Lim explained. "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."
Since the work was reported, Lim and his team have received inquiries from clinicians and scientists in several countries, including France, Israel and Australia, who are seeking to understand whether their patients' diseases could stem from genetic mutations that impair this newly identified function of RPA. With biochemical analysis, the researchers say they can test patient mutations to see whether they alter how RPA interacts with telomerase, potentially offering clearer explanations for affected families and guiding diagnostic decisions.
The study, titled Human RPA is an essential telomerase processivity factor for maintaining telomeres, was published in Science in 2025. According to the university, the work was supported by the U.S. National Institutes of Health as well as UW–Madison funding sources including the Office of the Vice Chancellor for Research, the Wisconsin Alumni Research Foundation and the Department of Biochemistry.
