Our DNA is compacted and arranged into chromosomes, most of which are shaped like X’s. The ends of the chromosomes' arms are protected with caps known as telomeres. Telomeres are made up of highly repetitive sequences of DNA, and they get shorter each time a cell divides, so they are thought to be closely linked to aging. Telomeres are critical to stability in the genome, and disease can arise when they malfunction.
New research reported in Science has indicated that errors in a protein that is vital to telomere maintenance could be connected to a range of diseases. This study may open up new diagnostic options for certain disorders such as bone marrow diseases and some cancers.
Telomerase is well known as an enzyme that helps maintain telomeres. In this study, the researchers used a program known as AlphaFold to search for proteins that interact with telomeres. This helped to determine whether these proteins might be related to diseases that are associated with abnormally short telomeres.
“This line of research goes beyond a biochemical understanding of a molecular process. It deepens clinical understanding of telomere diseases,” said senior study author Professor Ci Ji Lim of the University of Wisconsin–Madison.
The investigators revealed that a protein called replication protein A (RPA) can stimulate the telomerase enzyme, and therefore has a crucial role in telomere maintenance. The computational prediction was validated in cell lines. While RPA is well known for its DNA repair and replication roles, its telomere maintenance function is not as well established.
These findings may now help scientists learn more about diseases related to short telomeres, such as aplastic anemia, acute myeloid leukemia, and myelodysplastic syndrome.
“There are some patients with shortened telomere disorders that couldn’t be explained with our previous body of knowledge,” noted Lim. Some of these patients and their doctors have already contacted Lim for more information. “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.”
Sources: University of Wisconsin-Madison, Science
