RNA splicing is crucial for gene expression. After DNA is copied into messenger RNA (mRNA), noncoding parts called introns are removed, and the coding parts are spliced together.
This process is managed by a complex called the spliceosome. MIT biologists discovered a new regulation layer that helps determine which mRNA sites the spliceosome targets.
Their research shows that this regulation influences about half of all human genes and is found in animals and plants. This suggests that RNA splicing control is more complex than previously known.
MIT graduate student Connor Kenny explains that splicing in complex organisms like humans is more intricate than in simpler organisms like yeast despite being a conserved process. The human spliceosome has additional features that allow it to process specific introns more efficiently, enabling more complex gene regulation.
RNA splicing allows cells to control the content of mRNA transcripts, which carry instructions for building proteins.
mRNA transcripts contain coding regions called exons and noncoding regions called introns, with signals indicating where splicing should occur. This process allows a single gene to produce multiple proteins and change gene and protein size over time.
The spliceosome, a complex of proteins and small nuclear RNAs (snRNAs), forms on introns. Initially, an snRNA called U1 snRNA binds to the 5′ splice site at the start of the intron. It was previously thought that the binding strength between the 5′ splice site and U1 snRNA determined if an intron would be spliced out.
MIT researchers discovered that a family of proteins called LUC7 also influences splicing for up to 50% of introns in human cells. LUC7 proteins were known to associate with U1 snRNA, but their exact role was unclear. There are three LUC7 proteins in human cells. Two interact with a “right-handed” 5′ splice site, while the third interacts with a “left-handed” 5′ splice site.
The researchers found that about half of human introns have a right- or left-handed site, while LUC7 proteins do not control the other half. This additional regulation layer helps remove specific introns more efficiently.
Lead author Connor Kenny explains that this discovery shows the complexity of core splicing processes and highlights the need to examine these conserved molecular processes carefully.
Previous studies showed that mutations or deletions of a LUC7 protein linked to right-handed splice sites are associated with blood cancers, including about 10% of acute myeloid leukemias (AMLs). In this study, researchers found that AMLs missing a copy of the LUC7L2 gene had inefficient splicing of right-handed splice sites, leading to altered metabolism.
Understanding how the loss of the LUC7 protein affects splicing in AML could help design therapies that use these splicing differences to treat AML. Some small molecule drugs for other diseases, like spinal muscular atrophy, stabilize interactions between U1 snRNA and 5′ splice sites. Knowing that LUC7 proteins influence these interactions could improve these drugs’ specificity.
Researchers also found that plants have right- and left-handed 5′ splice sites regulated by Luc7 proteins. This splicing likely originated in a common ancestor of plants, animals, and fungi but was lost in fungi after they diverged.
Connor Kenny explains that our understanding of splicing comes from old yeast genetics work. Still, humans and plants have more complex splicing machinery with additional components that regulate different introns independently.
The team plans to analyze the structures formed by Luc7 proteins with mRNA and the spliceosome to understand how different forms of Luc7 bind to different 5′ splice sites.
Journal Reference:
- Kenny, C.J., McGurk, M.P., Schüler, S. et al. LUC7 proteins define two major classes of 5′ splice sites in animals and plants. Nat Commun 16, 1574 (2025). DOI: 10.1038/s41467-025-56577-4
