An international study led by CIC bioGUNE reveals the mechanism by which metabolites guide cellular decisions

The study, published in Nature, reveals that polyamines bind to specific protein domains and act as a metabolic shield against modifications in their structure

This mechanism is illustrated by the regulation of the spliceosome, a protein complex that determines the mature form and composition of RNAs, and connects metabolism with processes fundamental to the control of cellular identity and function

Polyamines are small molecules that occur naturally in all cells and are crucial for guiding cellular decisions, while an alteration in the abundance of these metabolites is invariably observed in pathological scenarios such as cancer or ageing. Despite decades of research, our knowledge of the mechanisms by which polyamines control cellular decisions is limited.

A collaborative study recently published in the prestigious journal Nature and led by a scientific team from CIC bioGUNE reports the discovery of a mechanism that reshapes our understanding of the actions of polyamines in health and disease. Using an integrated approach combining molecular simulations, biochemical and structural analyses, proteomics and cell assays, the research group identified that these metabolites alter the phosphoproteomic profile of tumour cells, with important repercussions for protein function. The study focuses on proteins involved in controlling RNA processing (alternative splicing), which leads to a remodelling of the RNA and protein repertoire in our cells. The research team succeeded in identifying the way in which polyamines recognise specific sequences in proteins and demonstrated that this process can be interrupted or enhanced by genetic or pharmacological strategies. With hundreds of proteins presenting potential polyamine-binding motifs, this study opens the door to a new understanding of polyamine-regulated cellular responses.

Polyamines are produced in excess in cancer, and their loss is associated with the ageing process. In turn, the inhibition of polyamine metabolism through pharmacological approaches has been evaluated in different types of cancer and is currently used as a therapeutic strategy in neuroblastoma. On the other hand, dietary supplementation with polyamines is proposed as an innovative strategy to counteract ageing. The findings of Zabala, Pujana and colleagues could help elucidate the effectors of polyamines in these processes, thus aiding in the design of new-generation dietary and pharmacological interventions.

The work was led by Dr. Arkaitz Carracedo, Ikerbasque research professor, head of the Cancer Cell Signalling and Metabolism Laboratory at CIC bioGUNE (member of BRTA) and group leader at CIBERONC, with Dr. Amaia Zabala-Letona and Dr. Mikel Pujana-Vaquerizo as co-first authors.