Home | News | A new mechanism discovered that helps cells prevent errors during DNA replication

From left: CNIO researchers Ana Losada, Daniel Giménez and Ana Cuadrado. /MadMoviex. CNIO

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.

Despite being essential for life, cell division continues to reveal unexpected mechanisms. An international team from the Institute of Molecular Cancer Research (IMCR) at the University of Zurich and the Spanish National Cancer Research Centre (CNIO) reports this week in Nature the discovery of a fundamental process that cells use during division to safeguard their genetic information.

The researchers found that cohesin, a key cellular protein, acts as a molecular anchor that helps reorganise newly replicated DNA and prevents potentially harmful errors when DNA replication encounters problems.

Cohesin: the protein that helps organise metres of DNA inside the cell nucleus

Cohesin is one of the most important proteins involved in cell division. Its function has been preserved throughout evolution, with cohesin proteins in organisms as distant as fungi and humans sharing remarkable similarities.

Until now, cohesin was mainly known for two essential roles. First, it holds together the two copies of each chromosome generated before cell division, ensuring their correct distribution into daughter cells. Second, it helps newly replicated DNA adopt the correct three-dimensional organisation inside the nucleus.

Both functions are crucial. DNA molecules are several metres long when fully extended, yet they must fit inside a microscopic nucleus. This requires precise folding, because the three-dimensional organisation of DNA influences how different regions of the genome communicate with one another.

“DNA folding by cohesin is not simply a way to make the molecule fit inside the nucleus. It brings together regions of the genome that may be far apart along the DNA sequence, allowing distant genes to coordinate their activity,” explains Ana Losada, head of the Chromosome Dynamics Group at CNIO.

A new role for cohesin: protecting genome stability

The idea that genome organisation influences gene activity has emerged relatively recently, and the role of cohesin in this process is an active area of research.

The new study published in Nature reveals an additional function for cohesin: protecting genetic material during DNA replication.

DNA replication is carried out by a complex molecular machinery that moves rapidly along DNA, generating two identical copies of each chromosome. However, this process can sometimes encounter obstacles or experience replication stress — for example, when the cell lacks enough molecular building blocks to complete the new DNA copy. As a result, replication can slow down or stop.

“If these interruptions are not properly managed, DNA can break or accumulate mutations that may contribute to diseases such as cancer,” explains Losada, senior co-author of the study. She was also who first identified cohesin in vertebrates in the late 1990s.

The researchers have now shown that cohesin is rapidly recruited to sites where DNA replication is disrupted. “Cohesin moves quickly to the affected region, providing stability and promoting a protective DNA organisation that preserves genome integrity,” says Losada.

The protein also prevents the activation of another factor, Primpol, which can restart DNA replication as an emergency response but may introduce a high number of genetic errors in the process.

Through these complementary actions, cohesin helps prevent genome instability.

A new genomic approach reveals cohesin’s protective role

The study is the result of a collaboration between the group of Massimo Lopes at the IMCR, which specialises in replication stress, and the group of Ana Losada at CNIO, which investigates cohesin biology.

The conception and much of the experimental work were led by postdoctoral researcher Daniel González (IMCR), who is also the corresponding author of the Nature paper.

A key element of the discovery was a new genomic approach developed by González (IMCR) and Daniel Giménez (CNIO), co-first authors of the study. The method maps the three-dimensional organisation of newly replicated DNA.

The genomic analysis was complemented by microscopy experiments showing that cohesin accumulates near newly replicated DNA when cells experience replication stress. The researchers also studied partially defective cohesin variants to identify which of its functions are required to protect DNA.

The work also involved the group of Javier Muñoz, a proteomics expert at the Biobizkaia Health Research Institute. Both González and Muñoz previously developed part of their scientific careers at CNIO.

Potential implications for precision oncology

The discovery identifies a fundamental cellular mechanism that could have implications for precision oncology. Many current cancer treatments work by inducing replication stress in tumour cells, ultimately causing DNA damage that leads to cell death.

“Understanding how cohesin protects replication forks could help develop combination therapies that disrupt this protective mechanism specifically in tumour cells while preserving healthy cells, potentially improving treatment effectiveness and reducing toxicity,” says Daniel Giménez.

Cohesin is also mutated in several cancer types, including Ewing sarcoma, bladder cancer and some myeloid leukaemias. The new findings could help clarify how alterations in cohesin influence patients’ responses to cancer treatments.

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