A newly discovered mechanism helps cells prevent errors during DNA replication
At the scale of individual cells, the human body is constantly in motion. Every second, millions of cells divide, particularly in tissues such as the bone marrow, intestine and skin; neurons and heart muscle cells divide far less frequently. All of this depends on the molecular machinery responsible for copying the billions of chemical units that make up DNA inside the nucleus.
A groundbreaking discovery published in Nature this week reveals how cells safeguard their genetic information during the replication of DNA, a process essential for life and fundamental to the functioning of the human body. Researchers from the Institute of Molecular Cancer Research at the University of Zurich and the Spanish National Cancer Research Centre have uncovered that a key cellular protein called cohesin plays a pivotal role in maintaining genomic stability.
Cohesin, a protein that has remained remarkably conserved throughout evolution from fungi to humans, has traditionally been known for two crucial roles in cell division: holding together the two copies of each chromosome and organizing newly replicated DNA within the nucleus. However, this new study demonstrates that cohesin also acts as a molecular anchor to reorganize DNA and prevent errors when replication encounters obstacles.
During DNA replication, which occurs millions of times daily in each cell, the protein complex responsible for copying the DNA can sometimes encounter difficulties, such as a shortage of necessary building blocks. This can lead to replication stress, where the process slows down or even stalls. If not properly managed, these interruptions can result in DNA breaks or mutations, potentially contributing to diseases like cancer.
The study reveals that cohesin rapidly moves to the sites where DNA replication is disrupted, providing stability and promoting a protective DNA organization that preserves the integrity of the genome. Furthermore, cohesin prevents the activation of another factor, PrimPol, which, although able to restart DNA replication during emergencies, can introduce a high number of genetic errors.
This discovery, the result of a collaboration between researchers at the IMCR and CNIO, highlights the fundamental role of cohesin in protecting the genome from instability. The findings have implications for precision oncology, as many cancer treatments induce replication stress in tumor cells to cause DNA damage and ultimately lead to cell death.
Understanding how cohesin protects replication forks could help develop targeted therapies that disrupt this protective mechanism specifically in tumor cells, reducing toxicity while improving treatment effectiveness.
The research also suggests that mutations in cohesin could influence the response to cancer treatments in certain types of cancer, including Ewing sarcoma, bladder cancer, and some myeloid leukemias. The study's methods, including a novel genomic approach to map the three-dimensional organization of newly replicated DNA and microscopy experiments, provide a deeper understanding of this critical cellular mechanism.
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