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A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans

Abstract

In many organisms, introducing double-stranded RNA (dsRNA) causes the degradation of messenger RNA that is homologous to the trigger dsRNA—a process known as RNA interference. The dsRNA is cleaved into short interfering RNAs (siRNAs), which hybridize to homologous mRNAs and induce their degradation1. dsRNAs vary in their ability to trigger RNA interference: many mRNA-targeting dsRNAs show weak phenotypes, and nearly all mRNAs of the Caenorhabditis elegans nervous system are refractory to RNA interference2,3,4. C. elegans eri-1 was identified in a genetic screen for mutants with enhanced sensitivity to dsRNAs. Here we show that eri-1 encodes an evolutionarily conserved protein with domains homologous to nucleic-acid-binding and exonuclease proteins. After exposure to dsRNA or siRNAs, animals with eri-1 mutations accumulate more siRNAs than do wild-type animals. C. elegans ERI-1 and its human orthologue degrade siRNAs in vitro. In the nematode worm, ERI-1 is predominantly cytoplasmic and is expressed most highly in the gonad and a subset of neurons, suggesting that ERI-1 siRNase activity suppresses RNA interference more intensely in these tissues. Thus, ERI-1 is a negative regulator that may normally function to limit the duration, cell-type specificity or endogenous functions of RNA interference.

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Figure 1: eri-1 encodes a DEMDh exonuclease that enhances sensitivity to GFP dsRNA in GABAergic neurons.
Figure 2: ERI-1 is an siRNase.
Figure 3: ERI-1 is localized in the cytoplasm of a subset of head and tail neurons.

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Acknowledgements

We thank J. Roig, G. Lenz and J. Avruch for reagents and advice; A. Frand for critically evaluating our manuscript; and members of the Ruvkun laboratory for advice and discussions.

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Correspondence to Gary Ruvkun.

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Kennedy, S., Wang, D. & Ruvkun, G. A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 427, 645–649 (2004). https://doi.org/10.1038/nature02302

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