Promiscuous splicing-derived hairpins are dominant substrates of tailing-mediated defense of miRNA biogenesis in mammals
Seungjae Lee,
David Jee,
Sid Srivastava,
Acong Yang,
Abhinav Ramidi,
Renfu Shang,
Diane Bortolamiol-Becet,
Sébastien Pfeffer,
Shuo Gu,
Jiayu Wen,
Eric C. Lai
Affiliations
Seungjae Lee
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA
David Jee
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA; Weill Graduate School of Medical Sciences, Weill Cornell Medical College, New York, NY 10065, USA
Sid Srivastava
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA; High Technology High School, Lincroft, NJ 07738, USA
Acong Yang
RNA Biology Laboratory, Center for Cancer Research, 8 National Cancer Institute, Frederick, MD 21702, USA
Abhinav Ramidi
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA; High Technology High School, Lincroft, NJ 07738, USA
Renfu Shang
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA
Diane Bortolamiol-Becet
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA; Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 Allée Konrad Roentgen, 67084 Strasbourg, France
Sébastien Pfeffer
Université de Strasbourg, Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 Allée Konrad Roentgen, 67084 Strasbourg, France
Shuo Gu
RNA Biology Laboratory, Center for Cancer Research, 8 National Cancer Institute, Frederick, MD 21702, USA
Jiayu Wen
Division of Genome Sciences and Cancer, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia; Corresponding author
Eric C. Lai
Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA; Weill Graduate School of Medical Sciences, Weill Cornell Medical College, New York, NY 10065, USA; Corresponding author
Summary: 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.
