Dicer uses distinct modules for recognizing dsRNA termini

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Science  19 Jan 2018:
Vol. 359, Issue 6373, pp. 329-334
DOI: 10.1126/science.aaq0921

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Substrate recognition by Dicer elucidated

The Dicer protein generates short RNAs from double-stranded RNA (dsRNA) substrates and is critical for RNA interference and antiviral defense. Sinha et al. report structures of a Drosophila Dicer protein that shed light on its two distinct mechanisms for recognizing and cleaving substrates: adenosine triphosphate (ATP)-independent, distributive cleavage of 3′-overhang dsRNAs and ATP-dependent, processive threading of blunt-end dsRNAs. This flexibility might provide invertebrates with the optimization capabilities needed for antiviral defense.

Science, this issue p. 329


Invertebrates rely on Dicer to cleave viral double-stranded RNA (dsRNA), and Drosophila Dicer-2 distinguishes dsRNA substrates by their termini. Blunt termini promote processive cleavage, while 3′ overhanging termini are cleaved distributively. To understand this discrimination, we used cryo–electron microscopy to solve structures of Drosophila Dicer-2 alone and in complex with blunt dsRNA. Whereas the Platform-PAZ domains have been considered the only Dicer domains that bind dsRNA termini, unexpectedly, we found that the helicase domain is required for binding blunt, but not 3′ overhanging, termini. We further showed that blunt dsRNA is locally unwound and threaded through the helicase domain in an adenosine triphosphate–dependent manner. Our studies reveal a previously unrecognized mechanism for optimizing antiviral defense and set the stage for the discovery of helicase-dependent functions in other Dicers.

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