Mutual feedback regulation between Poly(A)-specific ribonuclease (PARN) and cognate microRNAs

PARN regulates poly(A) lengths of pri-miR-29a and pri-miR-1207, which in turn target PARN mRNA. CPSF6 recruits PARN to pri-miRNAs, modulating miRNA levels and cell migration, revealing a dynamic mutual feedback between PARN and specific microRNAs. The majority of pri-miRNAs acquire a 5′ cap and 3′ poly(A) tail. Mature miRNAs recruit deadenylases that shorten poly(Α) tails triggering target mRNA degradation. Poly(A)-specific ribonuclease (PARN) is a deadenylase that also mediates late steps of noncoding RNA maturation. Herein, we show that PARN affects the expression of a subset of miRNAs in NCI-H520 cells of lung cancer origin, including miR-29a and miR-1207, which are also predicted to target PARN mRNA. PARN associates with pri-miR-29a and pri-miR-1207 regulating their poly(A) lengths. Conversely, miR-29a-3p and miR-1207-5p bind the 3′ UTR of PARN mRNA and regulate its expression. Cleavage and polyadenylation specificity factor 6 (CPSF6) recruits PARN to pri-miRNAs and together they affect primary and mature miR-29a-3p levels. Modulation of PARN, miR-29a-3p, or miR-1207-5p expression affects cell migration. We present a model to describe the dynamic relation between PARN and miR-29a and discuss its biological significance. Graphical Abstract lsa;9/5/e202503341/GA F1 GA