Abstract
MicroRNAs (miRNAs) are a class of short noncoding RNAs that can 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 exact reverse pairing of the 3’-ends of miRNAs or miRNA-like RNAs, collectively referred to as microsized RNAs (msRNAs), with template RNAs could initiate the production of msRNA-derived RNAs (msdRs), which consequently translate into msRNA-derived proteins (msdPs). Starting with 2,632 human miRNAs or miRNA-like msRNAs taken from the miRBase database, we predicted 11,121 and 1,239 unique msdRs and msdPs respectively using a 15-nt pairing threshold. We verified the authentic presence of example msdRs and msdPs in human cells. Of clinical relevance, we demonstrated that msdP0188 is highly expressed in human lung and breast cancer tissues and cells, and its corresponding msdRs represent novel anti-cancer targets. Intriguingly, inhibiting the human telomerase reverse transcriptase, a putative RNA-dependent RNA polymerase suggested by bioinformatic screening, led to reduced levels of msdP0188 in human cells. Our findings propose a novel “msRNA → msdR → msdP” axis that not only represents an augmentation to the central dogma of molecular biology but also predicts thousands of previously unknown RNAs and proteins that may have significant biological and pathological roles in human cells as well as in other biological systems.
One-Sentence Summary This work reports the discovery of msRNA-derived RNAs and proteins that may have significant roles in biology and medicine.
Competing Interest Statement
X.H., H.W., J.X., Y.E.C., and S.C. are co-inventors of a patent application that encompasses the predicted msdRs and msdPs described in this study. The other authors declare no competing interests.
Footnotes
We have modified some terminologies to describe our core findings more accurately. Besides, we have provided more computational and experimental data to support our claims.