Genome complexity: a new RNA, circular (Introduction)

by David Turell @, Tuesday, August 01, 2017, 18:35 (261 days ago) @ David Turell

Known about for many years but the function, if any is still unknown:

"Kadener’s work was published earlier this year,1 back-to-back in Molecular Cell with another group’s study—on human and mouse cells—that had simultaneously come to the same conclusion: translation of circRNAs can and does occur in living cells.2 For now, neither group has any hint of the function of these proteins, or of how common circRNA translation really is, but “you can imagine that it has some biological importance,” Kadener notes. RNA researcher William Jeck, currently a fellow at Harvard Medical School, agrees. Many scientists had “written off translation,” he says. “This is extremely exciting evidence that other circles may produce peptides that may be biologically relevant. . . . It’s really changed the paradigm.”


"Now, research on circRNAs is exploding, and the molecules’ biogenesis is gradually becoming clearer. At least two proteins, Muscleblind and Quaking, have been linked to circle formation, which generally occurs when the cell’s splicing machinery connects a downstream splice donor to an upstream splice acceptor, such as joining an exon’s 5´ end to its own 3´ end or an upstream exon’s 3´ end, in a process known as backsplicing. Recently, several additional mechanisms have been proposed (see “Making the Rounds” here), and some circRNAs contain introns, either instead of or in addition to exons. Regardless of their genetic makeup, the lack of ends makes circles less vulnerable to exonuclease enzymes, allowing them to persist in cells for days, unlike their linear counterparts, whose life spans are measured in hours or minutes.

"Despite a growing appreciation for the abundance—and now translation—of circRNAs in eukaryotes, there’s still very little understanding of what exactly circRNAs do. “We don’t even know how much of it is functional,” says Jeremy Wilusz, an RNA researcher at the University of Pennsylvania Perelman School of Medicine. “What’s the point of these circles? Why are they made?”


"CircRNAs also appear to associate with proteins, suggesting another suite of potential regulatory functions. For example, researchers recently showed that a circRNA produced by the Foxo3 gene (called circ-Foxo3) interacts with proteins involved in cell proliferation, including a key cyclin-dependent kinase and one of its inhibitors, suggesting a role in the cell cycle. And while most exon-containing circles accumulate in the cytoplasm, those that retain introns are often found in the nucleus, where they encounter proteins involved in transcription. In 2015, scientists in China showed that a group of exon-intron circRNAs promoted transcription of their parent genes via interaction with RNA polymerase II.10 Other studies have shown circles interacting with different RNA-binding proteins as well, including proteins now linked to circRNA biogenesis, such as Muscleblind and Quaking, and Argonaute proteins, well-known for their participation in RNAi-based gene regulation.


"Of course, how circRNAs come to be understood in the lab and possibly one day used in the clinic remains to be seen, as the study of these looped molecules represents an area that’s still young. But if the past five years are any indication, the study of circRNAs is rapidly ramping up. “What’s amazing to me is how fast this field has grown,” says Wilusz, whose lab supplies plasmids expressing circRNAs to other research groups and has recorded a dramatic uptick in requests in the last couple of years. “It’s really taking off.”

"Rajewsky, whose group is now focusing on circRNAs’ interactions in the brain, agrees that the best is very much ahead. “We’re really just at the beginning of an exciting journey,” he says. “It doesn’t happen often in molecular biology that you find such a fundamentally new phenomenon.'” 

Comment: So far some hints of gene regulation, but the overall reason for circRNA is still not clear.

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