(Press-News.org)
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.
A new layer of control revealed
Now, researchers led by Nicolas Thomä, who holds the Paternot Chair in Cancer Research at EPFL, 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, the team has revealed a new layer of control over this critical protein’s activity.
The researchers used a combination of cutting-edge techniques, including cryo-electron microscopy (cryo-EM), biochemical assays, and genome-wide mapping. Using these tools, they reconstructed how p53 binds to its DNA targets when those targets are wrapped up in nucleosomes.
They 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.
Other contributors
Friedrich Miescher Institute for Biomedical Research
University of Basel
Reference
Deyasini Chakraborty, Colby R. Sandate, Luke Isbel, Georg Kempf, Joscha Weiss, Simone Cavadini, Lukas Kater, Jan Seebacher, Zuzanna Kozicka, Lisa Stoos, Ralph S. Grand, Dirk Schübeler, Alicia K. Michael, Nicolas H. Thomä. Nucleosomes specify cofactor access to p53. Molecular Cell, 25 July 2025.
END
Ionic liquids (ILs) are a class of molten salts with a collection of exciting properties, which have been employed for wide-ranging applications across chemistry, biology, and materials science. However, their inherently high viscosity hampers the ability of molecular dynamics (MD) simulations to explore their structure-property relationships on large spatiotemporal scales. Coarse-grained (CG) models address this challenge by retaining essential structural features while eliminating some atomic details, significantly reducing ...
To the point
Energetic needs and social context shape aggression in female gorillas: A 25-year observational study of female gorillas shows that individual circumstances and social context can influence an individual's decision to engage in riskier aggressive behaviours.
Aggression and social hierarchy: While most aggression was directed from higher- to lower-ranking gorillas, 42 per cent of aggressive interactions were directed from lower to higher ranks – more than expected.
Taking risks: Female gorillas in reproductive ...
Autophagy is essentially the 'rubbish collection' of our cells. If there are problems in this process, which is so important for our health, diseases such as Parkinson's can result. In their latest study, leading cell biologists at the Max Perutz Labs at the University of Vienna investigated mitophagy – a form of autophagy – and came to a remarkable conclusion: the researchers have described a new trigger for mitophagy. This discovery has led to a reassessment of the hierarchy of factors ...
Northwestern University and University of California, Los Angeles (UCLA) scientists have developed a new process-based framework that provides a more accurate and dynamic approach to landslide prediction over large areas.
While traditional landslide prediction methods often rely solely on rainfall intensity, the new approach integrates various water-related processes with a machine-learning model. By accounting for diverse and sometimes compounding factors, the framework offers a more robust understanding of what drives these destructive events.
With further development, the new framework could help improve early warning systems, inform hazard ...
COLUMBUS, Ohio – An estimated 12% of first graders’ most-used media at home is educational, a new study suggests.
Results also showed that higher use of educational media was associated with both more time spent reading and less overall time in front of a screen – a signal that educational video, app and game use is not replacing reading.
A clearer picture of first graders’ TV or tablet time and factors related to their use of educational media may reveal opportunities for fitting ...
Psychological and philosophical studies have long shown that a person's subjective moods and emotions have a significant impact on how they experience the “meaning in life.” Philosopher Matthew Ratcliffe pointed out that a person’s mood vividly operates in the background of perception and plays a major role in how they grasp the meaning of their life.
In psychology as well, there have been empirical studies investigating how mood affects the perception of life’s meaning. Meanwhile, phenomenology has revealed that the lived, first-person experience of the body deeply influences the way we perceive ...
The origin of some neuropsychiatric diseases, such as autism, bipolar disorder, or depression, and certain neurodegenerative diseases, Alzheimer's and Parkinson's, can be found in very early stages of brain formation in the fetus. That is, earlier than previously recognized, according to a study by the Hospital del Mar Research Institute and Yale University, published in Nature Communications.
The work focused “on searching for the origin of mental illnesses in the earliest stages of fetal development, especially in the brain stem cells”, explains Dr. Gabriel Santpere, Miguel Servet researcher and coordinator of the Neurogenomics Research Group at ...
Apart from carrying the information to encode proteins in, RNA molecules can adopt intricate 2D and 3D structures. Specifically, the same RNA molecule can switch between ON and OFF structures, modulating the ability of ribosomes to bind to the RNA and translate it into proteins. A new study, led by University of Groningen molecular biologist Danny Incarnato and authored by postdoctoral researcher Dr Ivana Borovska, identifies hundreds of such regulatory RNA switches in E.coli bacteria and human cells. It was published in Nature Biotechnology on 25 July.
Several years ago, Incarnato developed a method to ...
Millions suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating condition often overlooked due to the lack of diagnostic tools, may be closer to personalized care, according to new research that shows how the disease disrupts interactions between the microbiome, immune system, and metabolism.
The findings—potentially relevant to long COVID due to its similarity with ME/CFS—come from data on 249 individuals analyzed using a new artificial intelligence (AI) platform that identifies disease biomarkers from stool, blood, and other routine lab tests.
“Our study achieved 90% ...
A new artificial intelligence model can improve the process of drug and vaccine discovery by predicting how efficiently specific mRNA sequences will produce proteins, both generally and in various cell types. The new advance, developed through an academic-industrial partnership between The University of Texas at Austin and Sanofi, helps predict how much protein cells will produce, which can minimize the need for trial-and-error experimentation, accelerating the next generation of mRNA therapeutics.
Messenger RNA (mRNA) contains instructions for which proteins to make and how to make them, enabling our bodies to grow and carry out the day-to-day ...
