LIN28 选择性调节一类 Let-7 微 RNA。
LIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs.
机构信息
Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA.
Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
出版信息
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.
LIN28 是一种二聚体 RNA 结合蛋白，可通过转录后抑制 let-7 微 RNA 的生成来调节发育并影响疾病状态。然而，let-7 抑制的机制仍不清楚，因为 LIN28 的识别依赖于锌指结构域（ZKD）和冷休克结构域（CSD）的协调靶向，而前体中 ZKD 结合 GGAG 样元件，CSD 的结合位点尚未得到系统表征。通过利用 LIN28 结合位点在体内的单核苷酸分辨率作图，我们确定 CSD 识别 (U)GAU 基序。该基序将 let-7 微 RNA 分为两类，即同时具有 CSD 和 ZKD 结合位点的前体（CSD）和仅具有 ZKD 结合位点的前体（CSD）。LIN28 在体内识别后，（CSD）前体的 3' 尿嘧啶化和降解更为有效，导致它们在 LIN28 激活的细胞和癌症中受到更强的抑制。因此，CSD 结合位点放大了 LIN28 的调节作用。
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