Molecular Biology

Dicing Triplets

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Science  09 Mar 2007:
Vol. 315, Issue 5817, pp. 1341
DOI: 10.1126/science.315.5817.1341c

Dicer, the endoribonuclease enzyme at the heart of RNA interference (RNAi), cleaves double-stranded RNA (dsRNA) and RNA hairpins to form small interfering RNAs (siRNAs) and microRNAs (miRNAs). The imperfect base-pairing of miRNA precursors requires that Dicer be fairly tolerant of mismatches in its substrates, and this in turn means that any RNA sequence that forms a passably presentable double helix can become a Dicer substrate.

Genes of the class of triplet-repeat expansion diseases, including Huntington's disease, contain stretches of CNG trinucleotide repeats that are dramatically expanded in afflicted individuals. Both the normal and expanded repeats are able to form hairpins in the messenger RNA (mRNA) in vitro. Are these repeats also substrates for Dicer? Krol et al. show that in vitro, Dicer can specifically cleave longer CNG hairpins both in isolation and in the local sequence context of mutant mRNAs. Furthermore, comparing mRNAs with normal and expanded repeats in cells from patients, Dicer selectively reduces the levels of mutant transcripts bearing the expanded numbers of repeats, generating siRNAs (“siCNGs”) that can trigger further rounds of cleavage. The same effect can be achieved by the introduction of exogenous siCNGs, suggesting possible therapeutic interventions based on RNAi-driven selective knockdown of the mutant mRNAs. — GR

Mol. Cell 25, 575 (2007).

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