Cancer cells can rework their own functions to grow faster and survive adverse conditions, for instance by increasing the production of specific proteins. Research could provide tools to interfere with these processes through RNA-based therapies. The latter could soon revolutionise medicine, thanks to their ability to directly influence gene expression and consequently the production of proteins within cells.

The research group led by Francesca Cutruzzolà of Sapienza University of Rome elucidated the details of a new mechanism to selectively block the activity of serine hydroxymethyltransferase (SHMT), a protein that plays a key role in tumour growth, using RNA as an inhibitory molecule. The research was carried out in collaboration with the Department of Chemistry and Technology of Drugs at Sapienza University of Rome, IBPM-CNR, the Universities of Milan and Pavia, and other national and international institutions.

Using cryoelectron microscopy, a state-of-the-art technique that allows molecules to be observed in their native state with unprecedented resolution, the researchers were able to observe the interaction between SHMT1 and RNA at the atomic level. This allowed a detailed understanding of the enzyme's mechanism of inhibition.

"This technique makes it possible to take a picture of an object more than a thousand times smaller than a single cell," says Sharon Spizzichino and Federica Di Fonzo of the Sapienza research group.

"The photograph at the atomic level of the interaction between RNA and metabolic proteins," explains Francesca Cutruzzolà, study coordinator, "represents an important milestone in biomedical research, opening the way to new frontiers in the treatment of diseases through innovative RNA-based therapies".

The findings pave the way for a deeper understanding of the molecular mechanisms underlying RNA therapies, which is crucial for the development of more effective and less invasive treatments for numerous disease conditions. The research was supported by AIRC and other funds such as those from the Piano nazionale ripresa resilienza (PNRR) allocated to the project entitled 'National Centre for Gene Therapy and Drugs based on RNA Technology'.

References:

Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1 - S. Spizzichino, F. Di Fonzo, C. Marabelli et al., Mol. Cell. - DOI:https://doi.org/10.1016/j.molcel.2024.06.016

Further Information

Francesca Cutruzzolà
Department of Biochemical Sciences "A. Rossi Fanelli"
francesca.cutruzzola@uniroma1.it