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One small step for worms, one giant leap for small RNAs

Nature Reviews Molecular Cell Biology volume 21, page 565 (2020)Cite this article

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Mapping a mutant phenotype to a DNA sequence used to be hard, but was rewarded by uncovering the protein responsible for the phenotype. Imagine then, identifying a gene’s sequence only to find no protein. Such was the outcome of the efforts of Lee et al. to define the sequence of lin-4, a locus that, genetically, represses the protein-coding gene lin-14. Downregulation of LIN‑14 is necessary for Caenorhabditis elegans development from the first larval stage (L1) to the second larval stage (L2). Undeterred, Lee, Ambros and colleagues went on to show that lin-4 produces two small RNAs, 22 and 61 nt long. The larger RNA could fold into a stem-loop structure, with the shorter RNA occupying the 5′ arm of the stem. Remarkably, the smaller RNA was predicted to base pair with seven sequence blocks in the 3′ untranslated region (3′ UTR) of lin-14.

Contemporaneously, Ruvkun and co-workers showed that gain-of-function mutations in lin-14 mapped to these same sequences, which were all conserved in related species. Earlier work from these investigators had shown that mutant alleles of lin-4 and gain-of-function alleles of lin-14, which still make mRNA in L2, have the same phenotype: reiteration of L1 instead of progressing to L2. Finally, the Ruvkun group showed that the lin-4-complementary sites mediated its function, suggesting that tiny lin-4 RNAs bound directly to lin-14 mRNA: adding just three of the sites from lin-14 to the 3′ UTR of a reporter mRNA allowed lin-4 to repress its translation into protein.

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References

Original articles

  • Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993)

    Article  CAS  Google Scholar 

  • Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993)

    Article  CAS  Google Scholar 

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  1. Howard Hughes Medical Institute and RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA

    Phillip D. Zamore

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  1. Phillip D. Zamore
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Correspondence to Phillip D. Zamore.

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Zamore, P.D. One small step for worms, one giant leap for small RNAs. Nat Rev Mol Cell Biol 21, 565 (2020). https://doi.org/10.1038/s41580-020-00281-2

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