摘要：SummaryMicroRNAs (miRNAs) are short double-stranded noncoding RNAs (19-23 nucleotides) that regulate gene expression by suppressing mRNAs through RNA interference. Targeting is determined by the seed sequence (position 2-7/8) of the mature miRNA. A minimal G-rich seed of just six nucleotides is highly toxic to cells by targeting genes essential for cell survival. A screen of 215 miRNAs encoded by 17 human pathogenic viruses (v-miRNAs) now suggests that a number of v-miRNAs can kill cells through a G-rich 6mer sequence embedded in their seed. Specifically, we demonstrate that miR-K12-6-5p, an oncoviral mimic of the tumor suppressive miR-15/16 family encoded by human Kaposi sarcoma-associated herpes virus, harbors a noncanonical toxic 6mer seed (position 3-8) and that v-miRNAs are more likely than cellular miRNAs to utilize a noncanonical 6mer seed. Our data suggest that during evolution viruses evolved to use 6mer seed toxicity to kill cells.Graphical AbstractDisplay OmittedHighlights•Tumor suppressive miR-15/16-5p with a toxic 6mer seed targets survival genes•kshv-miR-K12-6-5p, a paralog of hsa-miR-15/16-5p carries an offset toxic 6mer seed•A screen of 215 viral miRNAs identifies miRNAs that contain a toxic 6mer seed•Many human viral miRNAs have the capacity to kill through 6mer seed toxicityMolecular Genetics; Virology; Bioinformatics
