Amazing stuff!
"RNA splicing is a cellular process that is critical for gene expression. After genes are copied from DNA into messenger RNA, portions of the RNA that don’t code for proteins, called introns, are cut out and the coding portions are spliced back together.
This process is controlled by a large protein-RNA complex called the spliceosome. MIT biologists have now discovered a new layer of regulation that helps to determine which sites on the messenger RNA molecule the spliceosome will target.
The research team discovered that this type of regulation, which appears to influence the expression of about half of all human genes, is found throughout the animal kingdom, as well as in plants. The findings suggest that the control of RNA splicing, a process that is fundamental to gene expression, is more complex than previously known. ...
In the new study, the MIT team discovered that a family of proteins called LUC7 also helps to determine whether splicing will occur, but only for a subset of introns — in human cells, up to 50 percent.
Before this study, it was known that LUC7 proteins associate with U1 snRNA, but the exact function wasn’t clear. There are three different LUC7 proteins in human cells, and ... experiments revealed that two of these proteins interact specifically with one type of 5’ splice site, which the researchers called “right-handed.”
A third human LUC7 protein interacts with a different type, which the researchers call “left-handed.”
The researchers found that about half of human introns contain a right- or left-handed site, while the other half do not appear to be controlled by interaction with LUC7 proteins. ..."
From the abstract (poorly written, for experts only):
"Mutation or deletion of the U1 snRNP-associated factor LUC7L2 is associated with myeloid neoplasms, and knockout of LUC7L2 alters cellular metabolism.
Here, we show that members of the LUC7 protein family differentially regulate two major classes of 5′ splice sites (5′SS) and broadly regulate mRNA splicing in both human cell lines and leukemias with LUC7L2 copy number variation.
We describe distinctive 5′SS features of exons impacted by the three human LUC7 paralogs: LUC7L2 and LUC7L enhance splicing of “right-handed” 5′SS with stronger consensus matching on the intron side of the near invariant /GU, while LUC7L3 enhances splicing of “left-handed” 5′SS with stronger consensus matching upstream of the /GU.
We validated our model of sequence-specific 5′SS regulation both by mutating splice sites and swapping domains between human LUC7 proteins.
Evolutionary analysis indicates that the LUC7L2/LUC7L3 subfamilies evolved before the split between animals and plants. Analysis of Arabidopsis thaliana mutants confirmed that plant LUC7 orthologs possess similar specificity to their human counterparts, indicating that 5′SS regulation by LUC7 proteins is highly conserved."
Fig. 3: Regulation of splicing by LUC7 proteins depends on 5′SS handedness.
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