Recent discoveries in telomere biology reveal that the length and health of chromosome ends are regulated by enzymes telomerase and CST–Polα/primase, coordinated by the protein POT1, highlighting implications for treating telomere disorders and cancer.
The length of telomeres, which protect the ends of our chromosomes, must be carefully regulated. If they are too long, there is an increased risk of cancer; if they are too short, they lose their protective function, leading to telomere disorders that can have severe health implications.
Our cells prevent this excessive shortening by adding telomeric A recent study from the de Lange lab identified the CST–Polα/primase complex as the key regulator responsible for keeping that strand intact.
What remained to be seen was how CST, and its associated enzyme Polα-primase, travels to telomere to facilitate C-strand maintenance across replication cycles. Sarah Cai, a PhD candidate at Rockefeller, began investigating this piece of the telomere puzzle. Building on a decade of the de Lange lab’s groundwork on CST, Cai added cryo-EM to the techniques used in this study while being co-advised by Rockefeller’s Thomas Walz.
“The interdisciplinary nature of the study is one of the most exciting parts,” Cai says. “It was a very successful double-lab effort, making use of many different technologies.” Walz, whose research focuses on cryo-EM, noted how Cai incorporated AlphaFold, a deep-learning algorithm that can predict the unique 3D structures of proteins, into her work.
With the combined power of biochemistry, structural biology, and cell biology, the team ultimately confirmed that CST is recruited to telomeres by the POT1 protein. Once CST–Polα/primase is onsite, the addition and removal of phosphate groups from POT1 appears to function as an on/off switch that coordinates the final steps of telomere replication. Phosphorylated POT1 ensures that CST–Polα/primase remains inactive until telomerase has finished its job, upon which the dephosphorylation of POT1 activates CST–Polα/primase to add the finishing touches to the telomere.
Telomere disorders and cancer
Next, the team will look for specific enzymes that attach and remove phosphates during this process, controlling the on/off switch on POT1, and determining their role in regulating CST–Polα/primase recruitment and activity. A better understanding of how CST is recruited to the telomere cannot come fast enough for patients suffering from telomere disorders, such as Coats plus syndrome, a severe multi-organ disease characterized by abnormalities in the eyes, brain, bones, and GI tract.
“For a long time, we didn’t know why mild alterations in single DOI: 10.1016/j.cell.2024.05.002