Isn’t there always one person in a group of friends who’s a little weird or different? It turns out that AGO2, is a little different from its Argonaute paralogs, AGO1, 3, and 4. Researchers in Singapore are reporting that unlike other Argonautes, oddball AGO2 trims mammalian miRNAs, changing their functions during development.
The team knew that AGO2 was the only one of the four mammalian AGO paralogs that can cleave mRNAs, and that the 3’ ends of Argonaute-associated miRNAs are trimmed in Drosophila. But are 3’ ends of mammalian miRNAs trimmed too? And if so, is AGO2 involved?
The scientists found that when AGO2 was expressed in human cells, miR-124 was mostly in the form of 21-mers. But miR-124 was 22 nucleotides long when the other AGOs were expressed. miR-124s were 22-mers in embryonic mouse brains, but were mostly 21-mers in adults (which is when a higher proportion of Ago2 versus Ago1 was around). Synthetic miRNA 22-mers expressed along with AGO2 in human cells also wound up getting trimmed. And it wasn’t Dicer that was responsible—Dicer produced mostly 22-mers in vitro. That made the team suspect that Ago2 protein was cutting miR-124 after Dicer did its thing.
Studying the termini of other miRNAs throughout development led the researchers to conclude that their 3’ ends were getting clipped, just like in fruit flies. And it turns out that the PAZ domain in AGO2 is the likely culprit. They also found differences in neurite outgrowth in neuroblastoma cells depending on whether AGO1 or AGO2 was overexpressed, suggesting that trimming miRNAs has a biological effect.
Don’t be the odd one out—read Nucleic Acids Research, April 2012.