Discovery of microsized RNA-derived RNAs and polypeptides in human cells

MicroRNAs (miRNAs) are short noncoding RNAs that can regulate gene expression through the binding of their 5’-ends to mRNAs. However, the biological effects of miRNA binding via their 3’-ends remain unclear. Here, we discover that the exact reverse pairing of the 3’-ends of miRNAs or miRNA-like RNAs, collectively termed microsized RNAs (msRNAs), with template RNAs can initiate the production of msRNA-derived RNAs (msdRs), which can subsequently be translated into polypeptides (msdPs). Using 2,632 human msRNAs from miRBase, 11,121 msdRs and 1,239 msdPs were predicted based on a 15-nucleotide pairing threshold, and the presence of representative msdRs and msdPs was confirmed in human cells. Of clinical relevance, msdP0188 is highly expressed in human lung and breast cancers, and its corresponding msRNAs and msdRs represent novel anti-cancer targets. Notably, inhibiting telomerase reverse transcriptase, a putative RNA-dependent RNA polymerase identified by bioinformatic screening, led to reduced levels of msdP0188 in human cancer cells. Our findings reveal a novel “msRNA → msdR → msdP” axis, expanding the classical central dogma and predicting many previously unrecognized RNAs and polypeptides with potential biological functions in human cells and other systems.