Each cell in our body transports about two meters of DNA in its nucleus, wrapped in a small volume of a few hundred cubic micrometers, over a millionth of milliliter. The cell manages this by wrapping DNA strings around protein coils. Protein-ADN complexes are called nucleosomes and guarantee that DNA is safely stored.
But this packaging in nucleosomes also poses a challenge: important cellular machines must always access the genetic code to keep cells healthy and prevent diseases such as cancer.
One of the most important proteins of our cells is P53, the “genome guardian”. It helps control cell growth, triggers damaged DNA repair and can even control defective cells to self-destruction.
In many cancers, P53 is disabled or diverted, therefore understanding the functioning of the P53 is vital to develop therapies against cancer. But there is a problem: most DNA sequences that the P53 targets are buried inside nucleosomes, which makes them difficult to reach. Scientists have long wondered how P53 can reach these “hidden” sequences to do their job, as well as how other proteins interact with P53 manage to find it in this chromatin labyrinth.
A new layer of control revealed
Now, researchers led by Nicolas Thomä, who holds the Paternot pulpit in research on EPFL cancer, have discovered that nucleosomes act as a goalkeeper of P53 molecular partners. By studying how P53 interacts with different cofactors while being attached to nucleosomal DNA, the team revealed a new control layer on the activity of this critical protein.
The researchers used a combination of advanced techniques, including cryo-electronic microscopy (Cryo-EM), biochemical tests and cartography at the genome scale. Using these tools, they have rebuilt how the P53 binds to its DNA targets when these targets are wrapped in nucleosomes.
They then tested if two important “cofactors” proteins could still reach P53 when it is linked to nucleosomal DNA: USP7, which helps to stabilize P53, and the viral complex E6-E6AP, which helps to degrade P53.
They found that P53 can still be bonded at DNA even when it is wrapped in nucleosomes, especially on the edges where DNA enters or leaves the coil. But more surprising, the researchers discovered that the USP7 could interact with P53 even when it is linked to the nucleosome, forming a stable complex that they could observe in detail using cryo-EM.
On the other hand, E6-E6AP could not access P53 when it was attached to nucleosomal DNA. This means that the chromatin structure itself allows or prevents certain proteins from reaching P53, adding an additional 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 “control” access to P53, research opens up new possibilities in cancer research that could shed light on future therapies that aim to restore or control the P53 function in the disease.
