July 31, 2025

How DNA packaging controls the “genome’s guardian”

Our cells tightly pack DNA into structures called nucleosomes, which protect DNA but also hide important sites. The key cancer-fighting protein p53 can still access these hidden sites, especially at nucleosome edges. Researchers at the FMI and EPFL found that this DNA packaging controls which proteins can interact with p53, revealing new ways to understand and treat cancer.

Each cell in our bodies carries about two meters of DNA in its nucleus, packed into a tiny volume of just a few hundred cubic micrometers — about a millionth of a milliliter. The cell manages this by winding the strings of DNA around protein spools. The protein-DNA complexes are called nucleosomes, and they ensure that DNA is safely stored.

But this packaging into nucleosomes also poses a challenge: important cellular machinery must still access the genetic code to keep cells healthy and prevent diseases like cancer.

One of the most important proteins in our cells is p53, the “genome’s guardian.” It helps control cell growth, triggers repair of damaged DNA, and can even order faulty cells to self-destruct.

In many cancers, p53 is disabled or hijacked, so understanding how p53 works is vital for developing cancer therapies. But there’s a problem: most of the DNA sequences that p53 targets are buried inside nucleosomes, making them difficult to reach. Scientists have long wondered how p53 can reach those hidden sequences to do its job, as well as how other proteins that interact with p53 manage to find it in this maze of chromatin.

Now, researchers led by Deyasini Chakraborty and Colby Sandate, two researchers in the lab of Nicolas Thomä — who holds the Paternot Chair in Cancer Research at EPFL and is a guest scientist at the FMI, have found that nucleosomes act as a gatekeeper for p53’s molecular partners. By studying how p53 interacts with different cofactors while attached to nucleosomal DNA, Thomä’s team — in collaboration with the group of Dirk Schübeler at the FMI — has revealed a new layer of control over this critical protein’s activity.

This interdisciplinary team leveraged the joint Novartis-FMI cryo-electron microscopy facility and used a combination of cutting-edge techniques, including biochemical assays and genome-wide mapping, to reconstruct how p53 binds to its DNA targets when those targets are wrapped up in nucleosomes.

The researchers then tested whether two important cofactor proteins could still reach p53 when it is bound to nucleosomal DNA: USP7, which helps stabilize p53, and the viral E6-E6AP complex, which helps degrade p53.

They found that p53 can still bind to DNA even when it is wrapped in nucleosomes, especially at the edges where DNA enters or exits the spool. But more surprisingly, the researchers discovered that USP7 could interact with p53 even while bound to the nucleosome, forming a stable complex that they could observe in detail using cryo-EM. In contrast, E6-E6AP couldn’t access p53 when it was attached to nucleosomal DNA. This means that the structure of chromatin itself selectively allows or blocks certain proteins from reaching p53, adding an extra level of regulation beyond simple genetic sequences or protein-protein interactions.

The work shows that the physical structure of DNA and its packaging in the nucleus actively influences molecular interactions. By revealing how nucleosomes can gatekeep access to p53, the research opens new possibilities in cancer research that could inform future therapies that aim to restore or control p53 function in disease.

This story was originally published in EPFL News. It has been adapted to include additional details about the collaboration with the Schübeler lab at the FMI, the involvement of the Novartis-FMI cryo-EM facility, and Nicolas Thomä’s role as a guest scientist at the FMI.