An RNA-binding protein, Lin28, recognizes and remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs it regulates

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

20 Scopus Citations
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Author(s)

  • Elizabeth O'Day
  • Shunsuke Imai
  • Shen Mynn Tan
  • Rory Kirchner
  • Haribabu Arthanari
  • Oliver Hofmann
  • Gerhard Wagner
  • Judy Lieberman

Detail(s)

Original languageEnglish
Pages (from-to)17909-17922
Journal / PublicationJournal of Biological Chemistry
Volume290
Issue number29
Publication statusPublished - 17 Jul 2015
Externally publishedYes

Abstract

Lin28 is an evolutionarily conserved RNA-binding protein that inhibits processing of pre-let-7 microRNAs (miRNAs) and regulates translation of mRNAs that control developmental timing, pluripotency, metabolism, and tumorigenesis. TheRNA features that mediate Lin28 binding to the terminal loops of let-7 pre-miRNAs and to Lin28-responsive elements (LREs) in mRNAs are not well defined. Here we show that Lin28 target datasets are enriched for RNA sequences predicted to contain stable planar structures of 4 guanines known as G-quartets (G4s). The imino NMR spectra of pre-let-7 loops and LREs contain resonances characteristic of G4 hydrogen bonds. These sequences bind to a G4-binding fluorescent dye, N-methylmesoporphyrin IX (NMM). Mutations and truncations in the RNA sequence that prevent G4 formation also prevent Lin28 binding. The addition of Lin28 to a pre-let-7 loop or an LRE reduces G4 resonance intensity and NMM binding, suggesting that Lin28 may function to remodel G4s. Further, we show that NMMinhibits Lin28 binding. Incubation of a human embryonal carcinoma cell line with NMM reduces its stem cell traits. In particular it increases mature let-7 levels, decreases OCT4, HMGA1, CCNB1, CDK4, and Lin28A protein, decreases sphere formation, and inhibits colony formation. Our results suggest a previously unknown structural feature of Lin28 targets and a new strategy for manipulating Lin28 function.

Citation Format(s)

An RNA-binding protein, Lin28, recognizes and remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs it regulates. / O'Day, Elizabeth; Le, Minh T. N.; Imai, Shunsuke; Tan, Shen Mynn; Kirchner, Rory; Arthanari, Haribabu; Hofmann, Oliver; Wagner, Gerhard; Lieberman, Judy.

In: Journal of Biological Chemistry, Vol. 290, No. 29, 17.07.2015, p. 17909-17922.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review