LIN28 selectively modulates a subclass of let-7 microRNAs

Abstract

LIN28 is a bipartite RNA-binding protein that post-transcriptionally inhibits 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 family into Class I precursors with both CSD and ZKD binding sites and Class II precursors with ZKD but no CSD binding sites. LIN28 in vivo recognition--and subsequent 3' uridylation and degradation--of Class I 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 with potential implication in development and cancer.