Protein Dysfunction Could be the Cause of Diseases Resulting From Shortened Telomeres

New research from the University of Wisconsin–Madison reveals that dysfunction in a protein essential to maintaining stability in our chromosomes may be responsible for serious - and sometimes deadly - diseases.

Their findings, published today in Science, could provide patients and their doctors with new protein mutations to test for certain cancers and bone marrow diseases.

Our chromosomes (bundles of proteins and DNA that store all our genetic information), are protected from degradation by telomeres - the protective caps at the ends of chromosomes made from repetitive DNA sequences and proteins. While telomeres naturally shorten as we age, dysfunction in telomere formation and maintenance can make DNA less stable, leading to premature aging and other diseases.

Scientists in the laboratory of Ci Ji Lim, a UW–Madison professor of biochemistry, in collaboration with researchers in the university's Department of Chemistry, were interested in identifying proteins that interact with an enzyme called telomerase, which is responsible for maintaining telomeres. Malfunctions in these proteins could be the cause of some diseases resulting 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.

The researchers, led by graduate student Sourav Agrawal, research scientist Xiuhua Lin, and postdoctoral researcher Vivek Susvirkar, searched for proteins likely to interact with telomerase using AlphaFold, a machine learning tool that predicts the 3D structure of proteins and protein-protein interactions. They found that a molecule called replication protein A (RPA) plays an essential role in maintaining telomeres by stimulating telomerase. RPA's role in DNA replication and repair has long been understood, but its role in maintaining long, healthy telomeres in humans was previously unconfirmed. Guided by their findings from AlphaFold, the team experimentally validated that, in humans, RPA is required to stimulate telomerase and help maintain telomeres.

Their findings, Lim says, have immediate implications for some patients with often fatal illnesses resulting from 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."

Lim and his team have received inquiries from clinicians and scientists around the world asking if their patients' diseases could be the result of genetic mutations inhibiting RPA's newfound function.

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. 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."

Ci Ji Lim, professor of biochemistry, UW–Madison