Using mass spectrometry, ribosome profiling, and several CRISPR-based screens, Chen et al. identified 100s of previously uncharacterized functional micropeptides in the human genome. Protein translation outside of annotated open reading frames (ORFs) in messenger RNAs and within ORFs in long noncoding RNAs is pervasive. A functional screen using CRISPR-Cas9 with single-cell transcriptomics suggested critical roles for 100s of micropeptides. Micropeptides encoded by multiple short, upstream ORFs form stable protein complexes with the downstream canonical proteins encoded on the same messenger RNAs. One of the particularly puzzling things is that we’re seeing proteins that have real functions but do not seem to be evolutionarily conserved. Noncoding RNA may actually be coding.

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