LIN28 selectively modulates a subclass of let-7 microRNAs

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Ustinanenko, Dmytro ; Chiu, Hua-Sheng ; Treiber, Thomas ; Weyn-Vanhentenryck, Sebastien M ; Treiber, Nora ; Meister, Gunter ; Sumazin, Pavel ; Zhang, Chaolin (2018)

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 remains 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 3ʹ 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 effects of the LIN28 activation.
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