Reacción a "First mapping of the human spliceosome, the machinery that allows multiplying the variety of proteins from the same DNA"

The article is truly spectacular, both for the novelty of the discoveries and for their quality, complexity and relevance, as well as for the amount of original information it offers and for the new ways and means of study and analysis it makes available to researchers to advance in this field.

I know from colleagues in this area that Juan Valcárcel's laboratory has been working for years to complete this study, which due to its magnitude and complexity has surely cost a great effort and a considerable investment.

They really manage to show for the first time the mapping of the fundamental nucleus of the human spliceosome. Because of its degree of detail and depth, this map, together with the new molecular 'laws' and interactions that it has allowed them to discover, represents a real pillar to consolidate this new field of study that we can call spliceosomics, in which Valcárcel's laboratory is an internationally recognized pioneer.

Until now we knew in a more or less partial or fragmentary way how a limited (although increasing) number of the multiple components of the spliceosome (the splicing factors) influence the mechanisms of splicing [the process of cutting and splicing of RNA after DNA transcription] in the outcome of splicing. However, with this work they have tackled a monumental task, experimentally and systematically reducing the levels of 305 proteins involved in splicing (either in the central core of the machinery, the spliceosome, or in the constellation of factors that dynamically interact with it and regulate the splicing process), and then analyze the result of the absence or decrease of these proteins, i.e., what type of splicing mechanisms (there are four fundamental subtypes) increase or decrease in the absence of each of these 305 factors, which ultimately results in the formation of different protein variants with different functions. This is known to result in functional alterations that can lead to diseases such as cancer.

As is to be expected from a study published in this journal, the work presents a multitude of experimental verifications confirming the findings with different types of assays, which endorses its quality. In addition, the study fits superbly well with the knowledge available so far, while providing numerous original and relevant findings. Much of what we know about the functional and dynamic architecture of the spliceosome comes from electron cryomicroscopy studies, studies of protein interactions, functional and database annotations, etc. This study confirms with experimental data many of the theoretical predictions previously made, but also provides a remarkable amount of new findings that illuminate previously unknown structural and functional relationships and that will serve as a basis for further deepening the understanding of the spliceosome and deciphering how the splicing process functions and is regulated.

This is very relevant because the decision taken by the spliceosome within a cell to make one variant or another can determine whether a normal cell becomes cancerous or whether a neuron degenerates or dies. Therefore, knowing how the splicing machinery makes these decisions is crucial to identify new treatment targets and develop original therapeutic strategies for cancer, neurodegenerative pathologies or rare diseases.

The study does not present significant limitations, although by opening up so many new avenues it generates a multitude of unknowns that will have to be explored from now on. In fact, this is one of the virtues of the work, offering a large amount of information and laying the foundations for a comprehensive study of a lesser-known facet of the life of cells, how they decide to transform the information contained in a gene, which can give rise to a multitude of different proteins, into just one or a few variants with a specific function, and how this splicing process is altered in diseases.

One of the most curious and interesting findings is the demonstration of something that was already suspected, and that is that the splicing machinery has an amazing ability to regulate itself in a very complex and interconnected way. The functional meaning of this self-regulation is a challenge to be deciphered.

In the future, for example, it would be ideal to also extend this strategy to RNA types other than messenger RNA (encoding proteins) that also undergo the splicing process but are still much less well known, despite growing evidence of their relevance both in normal conditions and in numerous diseases.

Furthermore, there is the extraordinary challenge of deploying and extending the results of this study to understand in a complete and integrated manner the ultimate consequences of splicing alterations in the production of protein variants with specific functions, a task that will undoubtedly require highly complex experimental, technological and computational approaches.