Cohesin DNA Replication Discovery: Protein Guards Genome

Your body is copying DNA right now. Every second, millions of your cells divide, and every division needs an exact copy of the roughly three billion chemical letters in the human genome. A study published this week in Nature says one familiar protein does more than anyone realized when that copying runs into trouble.

The protein is called cohesin. Researchers at the University of Zurich and Spain's National Cancer Research Centre, known as the CNIO, found that cohesin rushes to spots where DNA replication stalls, anchors the newly copied strands, and stops a sloppier backup system from restarting the copy with errors. The discovery adds a third job to the two roles cohesin was already known for, and it makes this one of the most important recent findings in cohesin DNA replication research.

The protein that folds meters of DNA into a cell nucleus

Cohesin is one of the most durable pieces of machinery in biology. Versions of it appear in organisms as distant as fungi and humans, nearly unchanged across hundreds of millions of years of evolution.

Biologists already knew it for two essential roles. First, it holds together the two copies of each chromosome made before a cell divides, so the copies are handed out correctly to daughter cells. Second, it helps newly copied DNA fold into the right three-dimensional shape inside the nucleus. Uncoiled, a single DNA molecule would stretch several meters; folded, it fits inside a compartment you need a microscope to see. That folding also brings distant stretches of the genome into contact, which lets far-apart genes coordinate their activity, according to Ana Losada, who heads the Chromosome Dynamics Group at the CNIO.

What happens when the copy machine stalls

DNA replication is fast, but fragile. The molecular machinery that copies DNA can run out of building blocks or hit an obstacle, and replication then slows or stops entirely. Biologists call this replication stress.

The new work shows cohesin is quickly recruited to those stalled sites. "Cohesin moves quickly to the affected region, providing stability and promoting a protective DNA organization that preserves genome integrity," said Losada, the study's senior co-author, in a statement from the CNIO. Losada was also the researcher who first identified cohesin in vertebrates in the late 1990s.

There is a second part to the protection. When replication stalls, cells can call on an emergency restart factor called Primpol. Primpol gets the copying going again, but it introduces a large number of genetic errors along the way. The researchers found that cohesin also blocks Primpol from taking over, keeping the slower and more careful repair pathway in charge.

Through these two actions, cohesin helps prevent the genome instability that feeds cancer. "If these interruptions are not properly managed, DNA can break or accumulate mutations that may contribute to diseases such as cancer," Losada said.

How the team caught it in the act

The study grew from a collaboration between the group of Massimo Lopes at the Institute of Molecular Cancer Research in Zurich, which specializes in replication stress, and Losada's group at the CNIO, which studies cohesin biology. Much of the conception and experimental work was led by postdoctoral researcher Daniel Gonzalez, who is the paper's corresponding author.

A central element of the discovery was a new genomic method developed by Gonzalez and Daniel Gimenez of the CNIO, the study's co-first authors. The method maps the three-dimensional organization of DNA that has just been copied. The genomic analysis was backed by microscopy experiments showing that cohesin gathers near newly copied DNA when cells experience replication stress. The researchers also examined partially defective cohesin variants to pin down which of its functions are needed to protect DNA. The proteomics group of Javier Munoz at the Biobizkaia Health Research Institute also contributed to the work.

Why cancer researchers are paying attention

Many existing cancer treatments work by deliberately causing replication stress in tumor cells, damaging their DNA badly enough to kill them. A fuller picture of this cohesin DNA replication protection mechanism could point to combination therapies that knock out that shield inside tumors while sparing healthy cells, the researchers say.

"Understanding how cohesin protects replication forks could help develop combination therapies that disrupt this protective mechanism specifically in tumor cells while preserving healthy cells, potentially improving treatment effectiveness and reducing toxicity," said Gimenez.

The genome has other guardians under study too: researchers recently reported that the cancer protein BRD4 breaks a major rule about DNA, and that DNA keeps shifting during cell division. Cohesin is also mutated in several cancer types, including Ewing sarcoma, bladder cancer and some myeloid leukemias. The new findings may help clarify how those mutations shape patients' responses to treatment. The paper, by Gonzalez-Acosta, Gimenez-Llorente, Rodrigues and colleagues, is titled "Cohesin reshapes replication fork contacts to aid fork slowing and reversal" and appears in Nature.