Researchers at Rockefeller University have uncovered a key mechanism that helps maintain proper telomere length, a discovery that has significant implications for understanding and potentially treating various diseases, including cancer and telomere-related disorders.
The study, published in Cell, sheds light on how the CST–Polα/primase complex is recruited to telomeres, the protective caps at the ends of chromosomes, through chemical modifications of the POT1 protein.
Telomeres play a crucial role in protecting chromosome ends from degradation and ensuring genomic stability. Proper regulation of telomere length is vital, as excessively long telomeres can predispose to cancer, while excessively short telomeres can lead to serious health conditions known as telomere disorders. Researchers have long known that two enzymes, telomerase and the CST–Polα/primase complex, are essential for maintaining telomere length. However, the precise mechanism by which CST–Polα/primase is recruited to the telomere was previously unknown.
The team, led by Titia de Lange, the Leon Hess Professor at Rockefeller University, discovered that the recruitment of CST–Polα/primase is regulated by subtle chemical changes made to POT1, a protein in the shelterin complex involved in telomere maintenance. These findings offer new insights into the molecular details of telomere function and regulation.
“After the discovery of telomerase, it took decades to figure out how it gets to the telomere. Now, just months after discovering that CST–Polα/primase is the second critical enzyme required for telomere maintenance, we understand the details of how it is recruited,” said de Lange. “Moreover, we’ve found out how this process is regulated.”
The research focused on understanding how CST, along with its associated enzyme Polα-primase, is guided to the telomere to facilitate C-strand maintenance across replication cycles.
The team discovered that CST is brought to the telomeres by the POT1 protein. The addition and removal of phosphate groups from POT1 act as an on/off switch that coordinates the final steps of telomere replication. When POT1 is phosphorylated, CST–Polα/primase remains inactive until telomerase has completed its task. Dephosphorylation of POT1 then activates CST–Polα/primase to add the finishing touches to the telomere.
This regulatory mechanism is crucial for maintaining the balance of telomere length and has significant implications for diseases associated with telomere dysfunction. For instance, Coats plus syndrome, a severe multi-organ disease characterized by abnormalities in the eyes, brain, bones, and gastrointestinal tract, may be linked to disruptions in this telomere maintenance process.
The findings also have profound implications for cancer research. The de Lange lab has spent decades studying how telomere shortening contributes to tumor suppression and genome instability in cancer. This new understanding of telomere length regulation may help answer fundamental questions about tumor development and cancer prevention.
“Anything critical to telomere length regulation may well be critical to cancer prevention too,” de Lange said. “This is a major focus of our lab, and one of the reasons we’ll be looking into the interplay between CST–Polα/primase and telomerase more closely in the future.”
