Cowl artwork displaying the nucleosome being certain by varied cofactors and p53. Credit score: Colby R. Sandate (EPFL)
Every cell in our our bodies carries about two meters of DNA in its nucleus, packed right into a tiny quantity of just some hundred cubic micrometers—a couple of millionth of a milliliter. The cell manages this by winding the strings of DNA round protein spools. The protein-DNA complexes are known as nucleosomes, they usually be sure that DNA is safely saved.
However this packaging into nucleosomes additionally poses a problem: essential mobile equipment should nonetheless entry the genetic code to maintain cells wholesome and forestall illnesses like most cancers.
One of the crucial essential proteins in our cells is p53, the “genome’s guardian.” It helps management cell development, triggers restore of broken DNA, and might even order defective cells to self-destruct.
In lots of cancers, p53 is disabled or hijacked, so understanding how p53 works is significant for creating most cancers therapies. However there’s an issue: a lot of the DNA sequences that p53 targets are buried inside nucleosomes, making them troublesome to achieve. Scientists have lengthy questioned how p53 can attain these “hidden” sequences to do its job, in addition to how different proteins that work together with p53 handle to seek out it on this maze of chromatin.
A brand new layer of management revealed
Now, researchers led by Nicolas Thomä, who holds the Paternot Chair in Most cancers Analysis at EPFL, have discovered that nucleosomes act as a gatekeeper for p53’s molecular companions. By learning how p53 interacts with completely different cofactors whereas connected to nucleosomal DNA, the group has revealed a brand new layer of management over this crucial protein’s exercise. The paper is revealed within the journal Molecular Cell.
The researchers used a mixture of cutting-edge methods, together with cryo-electron microscopy (cryo-EM), biochemical assays, and genome-wide mapping. Utilizing these instruments, they reconstructed how p53 binds to its DNA targets when these targets are wrapped up in nucleosomes.
The nucleosome being certain by varied cofactors and p53. Credit score: Chakraborty et al 2025.
They then examined whether or not two essential “cofactor” proteins may nonetheless attain p53 when it’s certain to nucleosomal DNA: USP7, which helps stabilize p53, and the viral E6-E6AP complicated, which helps degrade p53.
They discovered that p53 can nonetheless bind to DNA even when it’s wrapped in nucleosomes, particularly on the edges the place DNA enters or exits the spool. However extra surprisingly, the researchers found that USP7 may work together with p53 even whereas certain to the nucleosome, forming a steady complicated that they might observe intimately utilizing cryo-EM.
In distinction, E6-E6AP could not entry p53 when it was connected to nucleosomal DNA. Which means that the construction of chromatin itself selectively permits or blocks sure proteins from reaching p53, including an additional degree of regulation past easy genetic sequences or protein-protein interactions.
The work exhibits that the bodily construction of DNA and its packaging within the nucleus actively influences molecular interactions. By revealing how nucleosomes can “gatekeep” entry to p53, the analysis opens new potentialities in most cancers analysis that might inform future therapies that goal to revive or management p53 perform in illness.
Extra info:
Deyasini Chakraborty et al, Nucleosomes specify co-factor entry to p53, Molecular Cell (2025). DOI: 10.1016/j.molcel.2025.06.027
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Chromatin group linked to p53 tumor suppression mechanism (2025, July 25)
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