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Role for a bidentate ribonuclease in the initiation step of RNA interference


RNA interference (RNAi) is the mechanism through which double-stranded RNAs silence cognate genes1,2,3,4,5. In plants, this can occur at both the transcriptional and the post-transcriptional levels1,2,5; however, in animals, only post-transcriptional RNAi has been reported to date. In both plants and animals, RNAi is characterized by the presence of RNAs of about 22 nucleotides in length that are homologous to the gene that is being suppressed6,7,8. These 22-nucleotide sequences serve as guide sequences that instruct a multicomponent nuclease, RISC, to destroy specific messenger RNAs6. Here we identify an enzyme, Dicer, which can produce putative guide RNAs. Dicer is a member of the RNase III family of nucleases that specifically cleave double-stranded RNAs, and is evolutionarily conserved in worms, flies, plants, fungi and mammals. The enzyme has a distinctive structure, which includes a helicase domain and dual RNase III motifs. Dicer also contains a region of homology to the RDE1/QDE2/ARGONAUTE family that has been genetically linked to RNAi9,10.

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Figure 1: Generation of 22-nucleotide sequences and degradation of mRNA by distinct enzymatic complexes.
Figure 2: Production of 22-nucleotide sequences by CG4792/Dicer.
Figure 3: Dicer participates in RNAi.

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We thank A. Nicholson for his gift of purified RNase III, and P. Fisher, M. McConnel and M. Pang for providing aid and materials for large-scale fly embryo culture. The Homeless clone was a gift from D. E. Gillespie and C. A. Berg. We also thank R. Kobayashi and R. Martiennsen for discussion and critical reading of the manuscript, and K. Velinzon for FACS. A.A.C. is an Anderson Fellow of the Watson School of Biological Sciences and a Predoctoral Fellow of the Howard Hughes Medical Institute. S.M.H. is a visiting scientist from Genetica, (Cambridge, MA). G.J.H. is a Pew Scholar in the biomedical sciences. This work was supported in part by grants from the NIH (G.J.H.).

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Bernstein, E., Caudy, A., Hammond, S. et al. Role for a bidentate ribonuclease in the initiation step of RNA interference . Nature 409, 363–366 (2001).

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