Tissue-specific 3 prime end-adenylation of miR-125b mediates cell survival

Next-generation sequencing has uncovered microRNAs (miRNAs) that undergo sequence modifications, known as isomiRs. Their physiological significance, however, remains uncertain, partly because they generally comprise a small fraction of total miRNAs. Here we report that more than 60% of miR-125b, one of the most abundant miRNAs in vascular smooth muscle cells (vSMC), exists as an edited isoform containing a non-templated adenosine residue at the 3 prime-end (miR-125b+A). The properties of miR-125b+A, such as stability and subcellular localization, are similar to those of canonical miR-125b, but miR-125b+A more potently inhibits the expression of a subgroup of targets, including the apoptosis effector Caspase-6 (CASP6). In the CASP6 transcript, adenylated miR125b preferentially targets a conserved, atypical site, with an unusual 36 nucleotides loop between seed sequence and 3 prime-end supplementary site. PAP associated domain containing 2 (PAPD2) is responsible for monoadenylation of miR-125b. Downregulation of PAPD2 results in the conversion of miR-125b+A to miR-125b, derepression of CASP6, and sensitization of vSMC to apoptotic stimuli. Thus, atypical site recognition by a tissue-specific isomiR fulfills a pro-survival role.