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Discovery and characterization of smORF-encoded bioactive polypeptides

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Abstract

Analysis of genomes, transcriptomes and proteomes reveals the existence of hundreds to thousands of translated, yet non-annotated, short open reading frames (small ORFs or smORFs). The discovery of smORFs and their protein products, smORF-encoded polypeptides (SEPs), points to a fundamental gap in our knowledge of protein-coding genes. Various studies have identified central roles for smORFs in metabolism, apoptosis and development. The discovery of these bioactive SEPs emphasizes the functional potential of this unexplored class of biomolecules. Here, we provide an overview of this emerging field and highlight the opportunities for chemical biology to answer fundamental questions about these novel genes. Such studies will provide new insights into the protein-coding potential of genomes and identify functional genes with roles in biology and disease.

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Figure 1: Overview of smORFs and SEPs.
Figure 2: Integrated genomic and proteomic discovery and validation of smORFs.
Figure 3: A bacterial smORF with metabolic function.
Figure 4: smORFs have varied functions in flies.
Figure 5: smORFs with functions in mice.
Figure 6: Potential impacts of chemical biology in smORF and SEP research.

Change history

  • 17 December 2015

    In the version of this article originally published in print, the citation for ref. 48 was omitted. It should have been cited as follows on p. 910 near the top right: "The translation of the uORFs regulates downstream ORF translation48 (Fig. 1c)." The error has been corrected in the online PDF and HTML versions of the article.

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Acknowledgements

The authors acknowledge support from the US National Institutes of Health (GM102491 to A.S.), The Leona M. and Harry B. Helmsley Charitable Trust (grant no. 2012-PG-MED002 to A.S.) and a Wellcome Trust Senior Fellowship (08756 to J.P.C.).

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Correspondence to Alan Saghatelian or Juan Pablo Couso.

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Saghatelian, A., Couso, J. Discovery and characterization of smORF-encoded bioactive polypeptides. Nat Chem Biol 11, 909–916 (2015). https://doi.org/10.1038/nchembio.1964

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