Scientists uncover a hidden protein behind deadly mystery diseases

The study, recently reported in Science, offers patients and clinicians new protein mutations to examine when diagnosing certain cancers and bone marrow disorders.

Understanding Telomeres and Chromosome Protection

Our chromosomes (bundles of proteins and DNA that store all our genetic information), rely on telomeres to prevent damage. These protective caps at each chromosome end are made from repetitive DNA sequences and proteins. Telomeres naturally shorten with age, but disruptions in how they form or are maintained can reduce DNA stability, which may accelerate aging or lead to disease.

Researchers working in the laboratory of Ci Ji Lim, a UW-Madison professor of biochemistry, along with collaborators in the university's Department of Chemistry, set out to identify proteins that interact with telomerase, the enzyme responsible for maintaining telomeres. Failures in these partner proteins could help explain diseases that arise from shortened telomeres.

"This line of research goes beyond a biochemical understanding of a molecular process. It deepens clinical understanding of telomere diseases," says Lim, whose work is supported by the National Institutes of Health.

Discovery of RPA's Essential Role in Telomere Maintenance

Graduate student Sourav Agrawal, research scientist Xiuhua Lin, and postdoctoral researcher Vivek Susvirkar led the search for proteins likely to work alongside telomerase. They used AlphaFold, a machine learning tool that predicts the 3D structure of proteins and protein-protein interactions. Their analysis highlighted a molecule called replication protein A (RPA) as a key factor in maintaining telomeres by stimulating telomerase. Although RPA has long been recognized for its involvement in DNA replication and repair, its importance in supporting healthy telomeres in humans had not been confirmed.

Using insights from AlphaFold, the team verified experimentally that, in humans, RPA is necessary to activate telomerase and preserve telomere length.

Implications for Patients With Short Telomere Disorders

Lim notes that these findings have direct relevance for people facing often deadly diseases caused by shortened 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," explains Lim. "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."

Global Interest and New Diagnostic Insights

Since publishing the work, Lim and his team have been contacted by clinicians and scientists from several countries seeking to understand whether their patients' illnesses could stem from genetic mutations that interfere with this newly identified function of RPA.

"There are colleagues reaching out from France, Israel, and Australia. They just want to give a cause for their patient's short telomere disease so that the patients and their families can understand what is happening and why," says Lim. "With biochemical analysis, we can test their patients' mutation to see if it impacts how RPA interacts with telomerase, and give the doctors insights into possible causes of their patients' diseases."

This research received support from the National Institutes of Health (R01GM153806 and DP2GM150023), the UW-Madison Office of the Vice Chancellor for Research, the Wisconsin Alumni Research Foundation and the UW-Madison Department of Biochemistry.