Biomolecular condensates and cancer

In a recent study, scientists have managed to go a step further in understanding the role played by biomolecular condensates –a new paradigm in biology– in the replication of the human papillomavirus (HPV), a mechanism common to a number of growing number of viruses and that could inspire new medicines.

In the last decade, a new paradigm emerged in biology, according to which the innumerable chemical processes that take place inside all cells are compartmentalized in liquid drops of different nature and complexity, which are called “biomolecular condensates” and They are the principle of membraneless organelles. These multiple compartments, which are similar to the drops that form in a vinaigrette, are transient (they form and dissolve according to chemical signals in cells), are usually made up of proteins and RNA or DNA, and play key roles in processes such as turning genes on and off, the cellular response to stress, neuronal synapses and carbon dioxide fixation in plants, among many other biological processes.

The Structure-Function and Protein Engineering Laboratory of the Fundación Instituto Leloir (FIL) in Argentina, directed by Dr. Gonzalo de Prat Gay, took a new step to better understand the molecular processes related to the replication of HPV, an agent responsible for cervical cancer, by demonstrating that the human p53 protein interacts by forming condensates with the E2 protein of the virus, both in vitro and in cells. And that this phenomenon can explain the mechanism by which p53 represses the replication of this virus whose oncogenic strains are responsible for cancer of the cervix, anus, and oropharyngeal cavity, among others. Dr. Silvia Borkosky is the lead author of the work published in the Journal of Molecular Biology.

“Our finding is possibly extensible to other similar DNA viruses that cause tumors. It is also the first time that p53 associated with a condensate has been described”, summarized Prat Gay to the CyTA-Leloir Agency.

The p53 protein is known as the “guardian of the genome”, since it is responsible for promoting the death of cells whose DNA has been altered by mutations, radiation, aging, viral infections, among other factors. Faced with severe damage, the role of p53 is to stop the cell cycle or activate the process called apoptosis, equivalent to cell suicide. This prevents the proliferation of damaged cells that can lead, for example, to cancerous processes. It is estimated that 50% of human cancers have a p53 mutation that prevents it from exercising its tumor suppressor function.

On the other hand, tumor-causing DNA viruses such as HPV destroy p53 so that the infected cell remains active and allows the virus to use the cellular machinery for self-perpetuation. “However, about 10 years ago it was shown that p53 can repress HPV replication and that it does so through its interaction with the E2 protein, the main regulator of the virus’s life cycle. Until now, the molecular mechanism behind this phenomenon was not known”, stated Prat Gay.

Condensates (droplets) of the human tumor suppressor protein p53 (magenta color) and the E2 viral replication protein of the HPV virus (green), cohabiting in the same condensate. (Image: CyTA-Leloir Agency)

The formation and dissolution of the drops or condensates that form inside the cells, and therefore their biological action, are governed by a physicochemical principle known as liquid-liquid phase separation. “This new knowledge unleashed a conceptual revolution in the organization of cell function in living beings,” emphasized Prat Gay, adding: “It is known that this mechanism is also involved in bacterial replication and in pathological situations such as those that occur in the Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS). Viruses, as parasites dependent on the cell’s chemical machinery to replicate, are no exception.

As the scientist indicates, in the last decade it was also revealed that granular structures in a large number of viruses known as replication sites or “viral factories” are liquid structures similar to membrane-less organelles, governed by the same physicochemical principles.

The new work will have implications in several fields in addition to HPV replication. It contributes to better understand fundamental mechanisms on the formation and regulation of biomolecular condensates present in an increasingly widespread diversity of functions and pathologies.

“Although an effective HPV vaccine exists today, the nature of the viral factories is common to a number of pathogens that do not yet have vaccines, including respiratory syncytial virus condensates and SARS-CoV-2, which we are investigating. at FIL”, explained Prat Gay, who concluded: “Condensates are emerging as new platforms for the search for antiviral drugs, and this extends to pathologies such as neurodegenerative diseases and cancer”. (Source: CyTA-Leloir Agency)