Cells have a built-in capacity limit for copying DNA, and it could impact cancer treatment

For almost 60 years, scientists have tried to understand why DNA doesn’t replicate wildly and uncontrollably every time a cell divides – which they need to do constantly. Without this process, we would die.

These essential, ongoing cell divisions involve a cell copying its unique genetic material, DNA, and then forming new cells. Cells know exactly when and how to do this during the roughly 24 hours it takes to complete a division, and they also know what type of cell they should become: a liver cell, a brain cell, or a skin cell.

If cells were to launch into random DNA replication, they would quickly run out of resources, and the timing could be disastrous. For example, all proteins and other components needed for division must be produced in the first hours and ready on the “spare parts shelf” before DNA replication begins.

Scientific studies over the last few decades have led scientists to realize that there had to be some limiting factor preventing cell replication from running rampant, wasting resources, and causing excessive copying errors. Something must prevent this catastrophic scenario known as the “the replication catastrophe” by biochemists and molecular biologists.

“If there were no brake of some kind, cells would become stressed, and cell division would fail or stop completely. If cell division in your body were left to itself without regulation, it would undermine the integrity of replicating our genome, causing disease like cancer,” explains Gita Chhetri, first author of the study and a PhD student in the Kumar Somyajit Laboratory at Department of Biochemistry and Molecular Biology, University of Southern Denmark.

The Kumar Somyajit Laboratory has led the work, focusing on DNA replication and genome integrity in mammalian cells. Several other research groups from the Department of Biochemistry and Molecular Biology contributed, along with colleagues from Université Paris-Saclay and the Institute of Biophysics of the Czech Academy of Sciences in Brno. The discovery has been published in Nature. Link: https://www.nature.com/articles/s41586-025-10011-3

The team now believes they have identified this limiting factor. The unexpected discovery came while the team members were studying replication mechanisms in dividing cells.

“Our group is dedicated to exploring and learning about DNA replication and considers our work fundamental research. But the significance of this finding means we must also consider its potential value in cancer treatment,” says Kumar Somyajit, Associate Professor and the research group leader.

How it works

When cells divide, they must first copy their DNA, so each new cell receives a complete genetic blueprint. But one side of the DNA is made in many short pieces, called Okazaki fragments, which must then be carefully processed and “stitched” together into a continuous DNA. This crucial step depends on PCNA, a clamp-like protein that sits on DNA and helps organize the proteins needed to complete replication.

In their scientific paper, the researchers describe how they found that this “stitching” process has a built-in limit in healthy cells. The team identified a protein, PAF15, as a natural brake that prevents the replication machinery from becoming overloaded and protects cells from the dangerous failure of replication catastrophe.

Interestingly, PAF15 is found only in higher animals, including humans, suggesting it is a relatively recent evolutionary innovation. Cells also produce only a limited amount of PAF15, and once that supply is used up, DNA replication must stop. Keeping PAF15 within a controlled range appears to be a fundamental way for cells to keep DNA replication balanced, safe, and under control.

In cancer cells, however, the picture is very different. Tumors often push DNA replication to the extreme in order to divide faster, and PAF15 can be present at much higher levels to support this rapid growth. But the researchers suggest this may also create a major vulnerability: by targeting this replication control system, it may selectively weaken—or even kill—rapidly dividing tumor cells.

The team now plans to expand studies to include experiments with cells from cancer patients, in collaboration with oncology researchers, Carla Maria Lourenco Alves and Henrik Jørn Ditzel at Department of Oncology, Odense University Hospital in Denmark.

“By studying these vulnerabilities through fundamental research, we can learn how to target and kill cancer cells more effectively. There are several types of medication that weaken a cancer cell’s ability to divide, but none that can completely kill cancer cells. Our hope is that this discovery could lead to a way to kill cancer cells more effectively. Indeed, devising strategies on overproducing PAF15 could naturally kill cancer cells by disrupting DNA replication,” concludes Kumar Somyajit.

The work in the Somyajit Group is supported by the Lundbeck Foundation Fellowship program, and project grants from the Danish Cancer Society and the Novo Nordisk Foundation. Kumar Somyajit also received a European Research Council Starting Grant.