A team from the Center for Genomic Regulation (CRG) in Barcelona details the first map of the human spliceosomethe most complex and intricate molecular machine within each cell. It has taken more than a decade to complete this scientific feat, which is published in the journal ‘Science’.
Its alteration is related to processes such as cancer, neurodegenerative processes or various rare diseases. According to the researchers, “by knowing exactly what each part does, we can find completely new angles to address a wide spectrum of diseases.”
The spliceosome, one of the most complex molecular machines in human biology, edits genetic messages transcribed from DNA, allowing cells to create multiple versions of proteins from a single gene. This process affects more than 90% of human genes and is linked to serious diseases such as cancer, neurodegenerative disorders and genetic conditions. Until now, the complexity and number of elements of the spliceosome had made it an enigma in biology.
CRG researchers discovered that the individual components of the spliceosome are highly specialized, which could unlock effective treatments with fewer side effects. “We now understand that the spliceosome is a set of finely calibrated tools, not just a cut-and-paste machine,” says Juan Valcárcel, leader of the research, revealing that some specific components could be transformed into new targets for drug therapy.
The spliceosome, the most complex molecular machine in human biology, coordinates the splicing process, crucial for RNA editing. This process eliminates non-coding segments, generating protein templates; Thus, with about 20,000 genes, the human body can produce more than 100,000 unique proteins. This set of 150 proteins and five small RNAs was found to have components with specialized roles and specific regulatory functions.
The CRG team demonstrated that each part contributes precisely to gene editing, revealing functional complexity that allows for unprecedented protein diversity, a discovery that researcher Malgorzata Rogalska describes as “an astonishing level of molecular specialization.”
The study revealed that manipulation of the SF3B1 component of the spliceosome, mutated in several types of cancer, such as melanoma and leukemia, causes a chain reaction in the cellular splicing network, taking it beyond its adaptive capacity and towards self-destruction.
For cancer
This finding suggests that attacking this interconnected network could be a “Achilles heel« in cancer cells, where the spliceosome is highly vulnerable. This advance offers new therapeutic opportunities by addressing defective RNA in splicing-related diseases, says Dom Reynolds of Remix Therapeutics, a company collaborating in the study.
In addition to its potential in oncology, this study offers hope for other disorders caused by errors in RNA splicing.
Valcárcel explains that the detailed map of the spliceosome, publicly available, facilitates the identification of specific errors in patient cellspromoting the development of personalized treatments for various diseases
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