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Spliceosomes, the molecular machines responsible for RNA splicing, play an important role in processing genetic information within our cells. These complexes remove non-coding sequences called introns from pre-messenger RNA (pre-mRNA), allowing the remaining exons to be spliced together to form mature messenger RNA (mRNA). This process ensures that the correct proteins are produced. However, the origin and evolution of spliceosomes and introns remain poorly understood.
In a recent study published in Genes and Development, Professor Manny Ares of the University of California, Santa Cruz, along with his team, has made a significant discovery that may offer insights into the evolutionary history of spliceosomes and their function in different species. The research reveals that spliceosomes may not only remove introns but also possess the ability to reinsert them into the genome.
The Mystery of Introns
Introns are DNA sequences that interrupt the coding regions of genes. The human genome contains hundreds of thousands of introns, averaging about seven or eight per gene. The spliceosome, an RNA-protein complex, is responsible for removing these introns and joining the exons together. Despite their prevalence, the evolutionary origin and function of introns remain enigmatic.
“I’m all about the spliceosome,” Ares said. “I just want to know everything the spliceosome does—even if I don’t know why it is doing it.”
Surprising New Role of the Spliceosome
Ares and his colleagues have discovered that after the spliceosome completes the splicing of pre-mRNA, it remains active and can engage in further interactions with the excised introns. This finding suggests that spliceosomes might reinsert introns into the genome, a function previously thought to be exclusive to Group II introns, which are mainly found in bacteria.
Group II introns can splice themselves out of RNA and reintegrate into DNA. These introns are believed to share a common ancestor with spliceosomes. While Group II introns can self-splice, the spliceosomal introns in higher organisms require the spliceosome for removal and were not thought to be reinserted into DNA. Ares's research indicates that spliceosomes might retain this ancient capability.
Investigating the Spliceosome's Function
To explore this hypothesis, Ares's lab conducted experiments in yeast cells, slowing down the splicing process to observe the behavior of spliceosomes after intron removal. They discovered that the spliceosome remains bound to the intron lariats and reshapes them into circular forms. A reanalysis of published RNA sequencing data from human cells confirmed that human spliceosomes exhibit similar behavior.
“We are excited about this because while we don't know what this circular RNA might do, the fact that the spliceosome is still active suggests it may be able to catalyze the insertion of the lariat intron back into the genome,” Ares said.
Testing the Hypothesis
To further investigate this possibility, Ares and his team aim to create an experimental setup where a spliceosome attached to a lariat intron is exposed to a DNA strand to see if it can insert the intron. This would provide proof of concept for their theory. They hypothesize that while this reinsertion might be rare in humans due to the high demand for spliceosomes, it could be more frequent in organisms with less active spliceosomes.
Cross-Disciplinary Collaboration
Ares is also collaborating with Professor Russ Corbett-Detig from the UCSC Biomolecular Engineering Department. Corbett-Detig's recent research, published in the Proceedings of the National Academy of Sciences (PNAS), systematically searched for new introns across various genomes. This study suggested that "burst" events in evolutionary history introduced numerous introns into genomes simultaneously.
Ares and Corbett-Detig are working to recreate such a burst event artificially to understand how genomes respond to sudden intron insertion. This collaboration combines their expertise to address the complex questions surrounding introns and spliceosomes.
“It is the best way to do things,” Ares said. “When you find someone who has the same kind of questions in mind but a different set of methods, perspectives, biases, and weird ideas, that gets more exciting. That makes you feel like you can break out and solve a problem like this, which is very complex.”