LIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs

Mol Cell. 2018 Jul 19;71(2):271-283.e5. doi: 10.1016/j.molcel.2018.06.029.


LIN28 is a bipartite RNA-binding protein that post-transcriptionally inhibits the biogenesis of let-7 microRNAs to regulate development and influence disease states. However, the mechanisms of let-7 suppression remain poorly understood because LIN28 recognition depends on coordinated targeting by both the zinc knuckle domain (ZKD), which binds a GGAG-like element in the precursor, and the cold shock domain (CSD), whose binding sites have not been systematically characterized. By leveraging single-nucleotide-resolution mapping of LIN28 binding sites in vivo, we determined that the CSD recognizes a (U)GAU motif. This motif partitions the let-7 microRNAs into two subclasses, precursors with both CSD and ZKD binding sites (CSD+) and precursors with ZKD but no CSD binding sites (CSD-). LIN28 in vivo recognition-and subsequent 3' uridylation and degradation-of CSD+ precursors is more efficient, leading to their stronger suppression in LIN28-activated cells and cancers. Thus, CSD binding sites amplify the regulatory effects of LIN28.

Keywords: CLIP; LIN28; bipartite binding; cancer; cold shock domain; let-7 microRNA biogenesis; selective suppression; stem cell.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Embryonic Stem Cells
  • Hep G2 Cells
  • Humans
  • K562 Cells
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Molecular
  • Nucleic Acid Conformation
  • Protein Domains
  • Protein Structure, Tertiary
  • RNA Precursors / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*


  • Lin-28 protein, mouse
  • Lin28A protein, human
  • MicroRNAs
  • RNA Precursors
  • RNA-Binding Proteins
  • mirnlet7 microRNA, human
  • mirnlet7 microRNA, mouse