Every cell in our our bodies carries about two meters of DNA in its nucleus, packed right into a tiny quantity of only a few hundred cubic micrometers—a few 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 make 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 stop illnesses like most cancers.
One of the vital essential proteins in our cells is p53, the “genome’s guardian.” It helps management cell development, triggers restore of broken DNA, and may 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 tough to achieve. Scientists have lengthy puzzled 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 staff has revealed a brand new layer of management over this vital 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.
They then examined whether or not two essential “cofactor” proteins might nonetheless attain p53 when it’s certain to nucleosomal DNA: USP7, which helps stabilize p53, and the viral E6-E6AP advanced, 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 might work together with p53 even whereas certain to the nucleosome, forming a steady advanced that they may observe intimately utilizing cryo-EM.
In distinction, E6-E6AP could not entry p53 when it was connected to nucleosomal DNA. Which means 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 reveals 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 would inform future therapies that goal to revive or management p53 operate in illness.
Extra data:
Deyasini Chakraborty et al, Nucleosomes specify co-factor entry to p53, Molecular Cell (2025). DOI: 10.1016/j.molcel.2025.06.027
Quotation:
Chromatin group linked to p53 tumor suppression mechanism (2025, July 25)
retrieved 27 July 2025
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