Promiscuous splicing-derived hairpins are dominant substrates of tailing-mediated defense of miRNA biogenesis in mammals

Cell Rep. 2023 Feb 28;42(2):112111. doi: 10.1016/j.celrep.2023.112111. Epub 2023 Feb 16.

Abstract

Canonical microRNA (miRNA) hairpins are processed by the RNase III enzymes Drosha and Dicer into ∼22 nt RNAs loaded into an Argonaute (Ago) effector. In addition, splicing generates numerous intronic hairpins that bypass Drosha (mirtrons) to yield mature miRNAs. Here, we identify hundreds of previously unannotated, splicing-derived hairpins in intermediate-length (∼50-100 nt) but not small (20-30 nt) RNA data. Since we originally defined mirtrons from small RNA duplexes, we term this larger set as structured splicing-derived RNAs (ssdRNAs). These associate with Dicer and/or Ago complexes, but generally accumulate modestly and are poorly conserved. We propose they contaminate the canonical miRNA pathway, which consequently requires defense against the siege of splicing-derived substrates. Accordingly, ssdRNAs/mirtrons comprise dominant hairpin substrates for 3' tailing by multiple terminal nucleotidyltransferases, notably TUT4/7 and TENT2. Overall, the rampant proliferation of young mammalian mirtrons/ssdRNAs, coupled with an inhibitory molecular defense, comprises a Red Queen's race of intragenomic conflict.

Keywords: CP: Molecular biology; TENT enzyme; TUTase; intragenomic conflict; microRNA; mirtron; ssdRNA; structured splicing-derived RNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Introns / genetics
  • Mammals / genetics
  • Mammals / metabolism
  • MicroRNAs* / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA Splicing* / genetics
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism

Substances

  • MicroRNAs
  • Ribonuclease III