Discovery of microRNA-derived RNAs and proteins in human cells

MicroRNAs (miRNAs) are a class of short noncoding RNAs that regulate gene expression through the binding of their 5’-end to mRNA. However, the biological effects of miRNA’s 3’-end binding to mRNA remain unclear. Here we discover that the pairing of miRNA’s 3’-end with RNA could serve as a primer to initiate the production of miRNA-derived RNAs (midRs), in the opposite direction of its originating RNA. midRs could consequently translate into miRNA-derived proteins (midPs). Starting from 2,656 Homo Sapiens miRNAs, we predicted 11,453 and 1,239 unique midRs and midPs for humans using a 15-nucleotide-pairing threshold. We verified the bona-fide existence of example midRs and midPs in human cells. Of clinical relevance, we demonstrate that midP0188 is highly expressed in human lung and breast cancer tissues and cells and that midP0188 and its encoding midRs represent novel anti-cancer targets. Our findings propose a miRNA→midR→midP axis that expands the central dogma and reveals thousands of novel RNAs and proteins that have immense potential for playing crucial biological and pathological roles in human cells, as well as other biological systems. ### Competing Interest Statement H.W., X.H., J.X., Y.E.C., and S.C. are co-inventors of a patent application covering the predicted midRs and midPs described in this work. The remaining authors declare no competing interests.