O'Day, ElizabethLe, MinhImai, ShunsukeTan, Shen MynnKirchner, RoryArthanari, HaribabuHofmann, OliverWagner, GerhardLieberman, Judy2019-10-052015O’Day, Elizabeth, Minh T. N. Le, Shunsuke Imai, Shen Mynn Tan, Rory Kirchner, Haribabu Arthanari, Oliver Hofmann, Gerhard Wagner, and Judy Lieberman. 2015. “An RNA-Binding Protein, Lin28, Recognizes and Remodels G-Quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates.” Journal of Biological Chemistry 290 (29): 17909–22. https://doi.org/10.1074/jbc.m115.665521.0021-92581083-351Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41483435Lin28 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. The RNA 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-methyl-mesoporphyrin 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 NMM inhibits 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.en-USJournal Article2019-10-0510.1074/jbc.M115.665521