Researchers have uncovered a previously unknown mechanism that safeguards the chromosome ends from being mistakenly repaired by the cell. While DNA repair is vital for survival, attempts to repair the chromosome ends – called telomeres – can have catastrophic outcomes for cells. The research, published in Nature, increases the understanding of how cancer and certain rare diseases develop. It was led by researchers at Linköping University in Sweden and the Institute of Cancer Research in the UK.

Cells constantly monitor their DNA. A DNA helix that ends abruptly is a signal that DNA has been severely damaged – at least in most cases.

“The most severe DNA damage a cell can suffer is when a DNA helix breaks up in two pieces,” says Francisca Lottersberger, associate professor at Linköping University.

Normally, the cells would try to promptly repair all damage to DNA. The dilemma is that our chromosomes have ends that look just like broken DNA. If cells were to “repair” them, looking for another loose end to join them with, this would lead to the fusion between two or more chromosomes, making the cell susceptible to transform into a cancer cell.

Therefore, the chromosome ends – called telomeres – must be protected from the cell’s DNA repair machinery.

“I’m very interested in the fact that the cells have to constantly repair DNA damages to avoid mutations, cell death, and cancer, while at the same time, they must not repair the chromosome ends by mistake since that would result in the same catastrophic outcome. What’s the difference between damaged DNA and the natural chromosome end? This problem has been known from almost a century, but some aspects are still not completely resolved,” says Francisca Lottersberger.

Although the telomeres are not to be repaired as if they were broken DNA, several DNA repair proteins can be found at the chromosome ends. Francisca Lottersberger’s research team has previously shown that a key repair protein, DNA Protein Kinase (called DNA-PK) helps in processing telomeres and in protecting them from degradation. But how DNA-PK at the same time is prevented from trying to repair these blunt DNA ends remained a mystery until now.

In collaboration with Dr. Max Douglas at the Institute of Cancer Research in the UK, the researchers have shown that two other proteins, called RAP1 and TRF2, have an important role to play in regulating DNA-PK.

“We show genetically, biochemically and structurally how the protein RAP1, brought to telomeres by TRF2, ensure by direct interaction that DNA-PK doesn’t ‘repair’ the telomeres,” says Francisca Lottersberger, who led the genetic part of the study.

The role of telomeres in processes such as cancer development and aging, and what happens when they do not work properly, has long interested scientists. Diseases caused by disturbances in telomere maintenance are rare, but very serious, and include premature aging, blood cell deficiency called aplastic anaemia and fibrosis in the lungs.

In about half of cases, the disease is explained by a known mutation that affects telomere stability, but in many cases, there is currently no known medical explanation for why the individual is sick. Francisca Lottersberger hopes that her findings will help in defining the biological mechanism behind more unexplained cases.

Their research is also relevant in cancer research. On one side, inappropriate “repair” of telomeres can trigger catastrophic events leading to the accumulation of mutations and cancer. On the other side, cancer cells are often less efficient at repairing damage to DNA compared to normal cells. This weakness is exploited in cancer treatments and many therapies kills tumour cells by causing DNA damage or inhibiting repair, or both.

In other words, knowledge of how cells regulate DNA repair and protect telomeres has a bearing on both prevention and treatment of cancer. Increased understanding of which proteins play key roles in these cellular processes can in the long term contribute to more precise and targeted treatment strategies.

Financial support for the study was provided by, among others, the Swedish Cancer Society, the Swedish Research Council and the Knut and Alice Wallenberg Foundation. Francisca Lottersberger works at the Wallenberg Centre for Molecular Medicine at Linköping University where she is a WCMM fellow.

Article: Chromosome end protection by RAP1-mediated inhibition of DNA-PK, Eickhoff, P., Sonmez, C., Fisher, C.E.L. et al, (2025). Nature, published 16 April 2025, doi: https://doi.org/10.1038/s41586-025-08896-1