The first blueprint of the human spliceosome, the most complicated and complex molecular machine found inside every cell, has been developed by researchers at the Centre for Genomic Regulation (CRG) in Barcelona. The scientific achievement, which took over ten years to accomplish.
Their findings were published in the journal Science.
By modifying genetic signals that are transcribed from DNA, the spliceosome enables cells to produce several protein variants from a single gene. The spliceosome is responsible for editing about 90% of human genes. Numerous illnesses, such as the majority of cancer types, neurological diseases, and genetic disorders, are associated with process errors.
The spliceosome has up until now remained elusive and unexplored in human biology due to the vast number of components involved and the complexity of its function.
Individual spliceosome components are significantly more specialized than previously believed, according to the plan. Due to the uncertain nature of their specialized roles, many of these components have not previously been taken into consideration for drug development. The finding may lead to the development of more potent and less harmful therapies.
The layer of complexity we’ve uncovered is nothing short of astonishing. We used to conceptualise the spliceosome as a monotonous but important cut and paste machine. We now see it as a collection of many different flexible chisels that allow cells to sculpt genetic messages with a degree of precision worthy of marble sculpting grandmasters from antiquity. By knowing exactly what each part does, we can find completely new angles to tackle a wide spectrum of diseases.
Juan Valcárcel
For proper operation, each and every cell in the human body depends on exact instructions from DNA. After being translated into RNA, these instructions go through a critical editing process known as splicing. Splicing creates a template or recipe for protein synthesis by cutting off non-coding RNA segments and sewing the remaining coding regions together.
Splicing enables the synthesis of at least five times as many proteins as humans’ about 20,000 protein-coding genes, and other estimates indicate that humans are capable of producing over 100,000 distinct proteins.
The precise functions of the spliceosome’s many components were not fully understood until recently. The spliceosome is a group of 150 distinct proteins and five tiny RNA molecules that coordinate the editing process. In order to observe the effects on splicing throughout the entire genome, the CRG team changed the expression of 305 spliceosome-related genes in human cancer cells one at a time.
Their research showed that the spliceosome’s many parts each have distinct regulatory roles. Importantly, they discovered that proteins at the heart of the spliceosome do more than just serve as inactive helpers; rather, they perform extremely specialized tasks that affect the processing of genetic signals and, in turn, the variety of human proteins.
One component, for instance, chooses which RNA fragment gets eliminated. While one component acts as a chaperone or security guard, preventing other components from acting too hastily and destroying the template before it is finished, another component makes sure cuts are made at the correct location in the RNA sequence.
The study’s authors liken their finding to a hectic post-production scene in a movie or television show, when genetic instructions derived from DNA are put together like uncut video.
You have many dozens of editors going through the material and making rapid decisions on whether a scene makes the final cut. It’s an astonishing level of molecular specialisation at the scale of big Hollywood productions, but there’s an unexpected twist. Any one of the contributors can step in, take charge, and dictate the direction. Rather than the production falling apart, this dynamic results in a different version of the movie. It’s a surprising level of democratization we didn’t foresee.
Dr. Malgorzata Rogalska
The study’s most important conclusion is that the spliceosome is extremely interconnected, and that altering one part can have far-reaching consequences for the entire network.
For instance, the study altered SF3B1, a spliceosome component known to be mutated in a variety of malignancies, such as breast cancer, leukemia, and melanoma. Anti-cancer medications also target it, albeit the precise mechanisms of action have not yet been determined.
According to the study, SF3B1 expression changes in cancer cells trigger a series of events that impact one-third of the cell’s splicing network, leading to a series of failures that overwhelm the cell’s capacity to support growth.
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The discovery is encouraging because conventional treatments, such those that target DNA abnormalities, frequently make cancer cells resistant. Rewiring their splicing machinery is one way tumors adapt. Diseased cells may self-destruct as a result of targeting splicing pushing them over a tipping threshold that cannot be compensated for.
Cancer cells have so many alterations to the spliceosome that they are already at the limit of what’s biologically plausible. Their reliance on a highly interconnected splicing network is a potential Achilles’ heel we can leverage to design new therapies, and our blueprint offers a way of discovering these vulnerabilities.
Juan Valcárcel
This pioneering research illuminates the complex interplay between components of the spliceosome, revealing insight into its mechanistic and regulatory functions. These findings not only advance our understanding of spliceosome function but also open potential opportunities to target RNA processing for therapeutic interventions in diseases associated with splicing dysregulation.
Dom Reynolds
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Numerous additional illnesses, besides cancer, are brought on by defective RNA molecules that result from splicing errors. Researchers can now assist in determining precisely where splicing faults are occurring in a patient’s cells thanks to a comprehensive map of the spliceosome that the study’s authors have made publicly available.
We wanted this to be a valuable resource for the research community,
Drugs correcting splicing errors have revolutionised the treatment of rare disorders like spinal muscular atrophy. This blueprint can extend that success to other diseases and bring these treatments into the mainstream,
Juan Valcárcel
Current splicing treatments are focused on rare diseases, but they are just the tip of the iceberg. We are moving into an era where we can address diseases at the transcriptional level, creating disease-modifying drugs rather than merely tackling symptoms. The blueprint we’ve developed paves the way for entirely new therapeutic approaches. It’s only a matter of time.
Dr. Malgorzata Rogalska
Source: Centre for Genomic Regulation – News
Journal Reference: Rogalska, Malgorzata E., et al. “Transcriptome-wide Splicing Network Reveals Specialized Regulatory Functions of the Core Spliceosome.” Science, 2024, DOI: https://doi.org/10.1126/science.adn8105.
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