Researchers at the University of Wisconsin–Madison have discovered that malfunctions in a protein responsible for maintaining the stability of human chromosomes may be the cause of serious and sometimes fatal diseases. The study, published in Science, could help doctors and patients identify new protein mutations associated with certain cancers and bone marrow disorders.

Chromosomes are tightly packed complexes of DNA and proteins that contain all our genetic information. Their ends are protected by telomeres — specialized “caps” made of repeating DNA sequences and proteins. Telomeres naturally shorten with age, but errors in their formation or maintenance can destabilize DNA, leading to premature aging and disease.

The research team, led by Professor Qi Ji Lim from the Department of Biochemistry, in collaboration with scientists from the Department of Chemistry, studied proteins that interact with telomerase — the enzyme responsible for maintaining telomere length. Disruptions in these proteins can trigger disorders linked to shortened telomeres.

Using AlphaFold, a machine-learning system that predicts the 3D structure of proteins and their interactions, the team identified Replication Protein A (RPA) as a key factor in telomere maintenance. RPA has long been known for its role in DNA replication and repair, but its involvement in maintaining long, healthy human telomeres had not been previously confirmed. Experimental validation revealed that RPA is indeed essential for stimulating telomerase activity and preserving telomere integrity.

This discovery has direct implications for patients suffering from conditions caused by shortened telomeres — including aplastic anemia, myelodysplastic syndrome, and acute myeloid leukemia. According to Lim, many patients with telomere-related disorders previously had no explanation based on known genetic data, but it now appears that mutations impairing RPA’s ability to stimulate telomerase could be responsible.

Researchers have already received inquiries from clinicians and scientists worldwide seeking to determine whether their patients’ diseases might be linked to genetic mutations that block RPA function.