A newly discovered mechanism reveals how cells safeguard their genetic material during DNA replication, a process essential for cell division. Scientists from the Institute of Molecular Cancer Research (IMCR) at the University of Zurich and the Spanish National Cancer Research Centre (CNIO) have uncovered a fundamental role for a protein called cohesin, which helps prevent errors in DNA replication. Their findings, published in the journal Nature, show that cohesin acts like a molecular anchor, reorganizing newly copied DNA and protecting it when replication faces challenges. This discovery adds to our understanding of how cells maintain genomic stability, a crucial factor in preventing diseases like cancer. Cohesin is a vital protein involved in cell division, found in organisms ranging from fungi to humans. Until now, it was primarily known for two roles: first, holding together the two copies of each chromosome before they are distributed to daughter cells, and second, helping newly replicated DNA fold correctly within the cell nucleus. DNA molecules are incredibly long—several meters when fully stretched—so they must be carefully folded to fit inside the tiny nucleus. This folding is not just for space; it allows distant parts of the genome to interact, influencing how genes are expressed and regulated. The new study reveals an additional role for cohesin: protecting DNA during replication. The process of DNA replication is fast and complex, but it can be interrupted by obstacles or stress, such as a lack of essential building blocks. These interruptions can cause DNA breaks or mutations, which may lead to diseases like cancer. The researchers found that when replication is disrupted, cohesin quickly moves to the affected area, stabilizing the DNA and preventing errors. It also suppresses a protein called Primpol, which can restart replication but may introduce harmful mutations. This dual action by cohesin helps maintain the integrity of the genome. The discovery was made using a new genomic approach developed by researchers Daniel González (IMCR) and Daniel Giménez (CNIO), who are co-first authors of the study. Their method maps the three-dimensional structure of newly replicated DNA, revealing how cohesin organizes it. Microscopy experiments confirmed that cohesin accumulates near DNA when replication stress occurs. The study also examined cohesin variants with partial defects to determine which functions are essential for DNA protection. The research involved collaboration with experts in proteomics, including Javier Muñoz from the Biobizkaia Health Research Institute. This discovery has potential implications for cancer treatment, particularly in the field of precision oncology. Many cancer therapies target replication stress in tumor cells, causing DNA damage and cell death. Understanding how cohesin protects DNA could lead to new treatment strategies that specifically disrupt this protection in cancer cells, improving the effectiveness of therapies while minimizing harm to healthy cells. Cohesin mutations are also linked to certain cancers, such as Ewing sarcoma and some types of leukemia, suggesting that this research could help explain how these mutations affect treatment outcomes.