New light has been shed on the molecular mechanisms that regulate extra-chromosomal DNA in tumours: this is the result of a study led by a research group from the National Institute for Nuclear Physics (INFN) and the University of Naples Federico II, which used polymer physics models to explore the complex organisation and behaviour of extra-chromosomal DNA. The study, which combines the tools of molecular biology and theoretical physics to investigate the mechanisms involved in tumour processes, was recently published in Nature Communications.
Cancer cells may contain small circular DNA molecules located outside the normal chromosomes, known as ecDNA (extra-chromosomal circular DNA). ecDNA can carry oncogenes, genes that in healthy cells help regulate cell growth but that, when they become overactive or escape normal control mechanisms, can promote tumour development. Together with DNA regulatory elements, ecDNA can further enhance their activity, driving tumour cell growth and increasing resistance to therapy. Understanding the mechanisms that govern the behaviour of ecDNA is therefore of great interest for fundamental biomedical research.
“In our study, we used polymer physics models to describe the interactions between ecDNA and BRD4, a protein involved in the regulation of gene expression,” explains Mario Nicodemi, INFN researcher and professor at the University of Naples Federico II, who led the research. “Thanks to its ability to mediate interactions between DNA molecules and other proteins, BRD4 can promote the formation of biomolecular condensates, highly dynamic structures that serve to rapidly concentrate molecules and organise reactions, and which may therefore play a significant role in tumour evolution. Clarifying what these interaction mechanisms are is therefore of fundamental importance for understanding how they can be interfered with, and consequently how oncogenes in these tumour cells can be deactivated,” Nicodemi concludes.
The work shows that these interactions lead to the spontaneous aggregation of ecDNA within the cell nucleus through a phase-separation process, inducing the formation of ecDNA condensates. Within these condensates, interactions between different ecDNA molecules bring specific oncogenes into contact with DNA sequences that promote their activation, increasing their activity well beyond what would simply result from the increased number of gene copies in the system. The model’s predictions regarding the structure of the condensates were confirmed in the laboratory by experimental data from tumour cells.
The research also analysed the effects of JQ1, a molecule that interferes with the activity of the BRD4 protein and therefore with ecDNA phase separation. In this case as well, the model’s predictions, according to which JQ1 disperses the condensates and therefore reduces the expression of ecDNA oncogenes, were confirmed experimentally.
The study thus demonstrates how theoretical physics can become a valuable tool for unveiling the mechanisms underlying the organisation and activity of ecDNA, opening up new perspectives for identifying strategies aimed at interfering with the processes that sustain their activity.
