Traffic jams at DNA ends and how cells cope with that

Telomeres are protective structures found at the ends of chromosomes. Much like the plastic tips on shoelaces, they prevent chromosomes from fraying, sticking together, and degrading. Telomeres are made up of a short DNA sequence - six base pairs long - that is identical in all humans and repeated thousands of times. Each time a cell divides and copies its DNA, the telomeres shorten a bit. When they become too short, the cell can no longer divide. In this way, telomeres determine a cell’s fate, and their length is a biomarker for age.

Because of the repetitive sequence and the fact that they do not encode for proteins, telomeres were once considered of little interest by many biologists. Anabelle Decottignies thought differently. She got fascinated by the mysterious structures and their role in genomics. She decided to study them when she started her research group at the de Duve Institute in 2004. A bold choice that has turned out very well.

Much has been learned about telomeres since then and the group of Anabelle Decottignies has made important contributions to that. Telomeres are involved in many cancer types, where tumor cells have gained the ability to maintain the length of their telomers, allowing them to divide endlessly. The work of Anabelle Decottignies has led to a better understanding of the mechanisms that cancer cells apply to escape telomere shortening. Their research has also led to valuable insights into the evolvement of telomere length during life and its role in aging. Her work has been recognized by multiple awards, such as the Allard-Janssen Prize and the Oswald Vander Veken Prize.

In a recent line of research, the team dove deep into the fundamentals of telomere copying, specifically focusing on the challenges posed by long telomeres. During DNA copying, the double DNA strand is unzipped and each separated strand then serves as a template for the synthesis of a new double strand. Telomeres are also copied, but here the replication and repair mechanisms easily make mistakes due to both their location at the end and their guanine-rich content. To prevent these mistakes, telomeres are covered by a protein complex called shelterin. “The telomeres have blocks that hinder copying, like traffic jams on a highway. The longer the telomere, the more blocks there are, making long telomeres particularly difficult to copy. Cells have various ways to alleviate these traffic jams. One involves a protein called TRF1, which is part of the shelterin complex. It was unclear how TRF1 does this,” Anabelle Decottignies explains.

To unravel this, her team worked with human cells carrying chromosomes with different telomere lengths. Using molecular biology approaches and fluorescence microscopy, they analyzed the sizes and structures of the telomeres as well as the presence of proteins that indicate copying problems. They worked together with research groups in Milan and Lisbon. “In the lab, we cannot measure the speed at which telomeres get copied directly, but we can detect indicators that reveal how smoothly - or how poorly - the process is proceeding”, says Anabelle Decottignies.

With these techniques, the team made an unexpected discovery. Anabelle Decottignies: “We found that TRF1 does not work by eliminating the blocks, as has been hypothesized for some time, but by slowing down the copying. The slower pace makes the process go smoothly and it avoids stops.” They also uncovered why this mechanism does not work well when telomeres are long. “There is only a limited amount of TRF1 in a cell. If telomeres are long, they are not fully covered by TRF1 and thus not well protected. When extra TRF1 is added, telomeres become covered and the copying goes better.”

This protective role of TRF1 is essential. “A genetic mutation that results in the complete absence of TRF1 is lethal—an embryo carrying such a mutation cannot survive to birth”, Anabelle Decottignies explains. By contrast, other inherited mutations that disrupt telomere replication can allow individuals to be born, but with abnormally short telomeres. These individuals often experience severe health complications throughout life and typically have a reduced life expectancy. “Understanding how telomeres are replicated is therefore important. We have developed a tool to measure telomere length, which is used in Saint-Luc Hospital to diagnose patients with short telomere syndromes. This will give us valuable insights that will hopefully lead to the development of better cures.”

Article describing this research

TRF1 relies on fork reversal to prevent fragility at human telomeres

Vaurs M, Claude E, Zanella E, Rodrigues J, Nassour J, Karlseder J, Azzalin CM, Doksani Y, Decottignies A

Nat Commun (2025) 16(1):6439