Example：10.1021/acsami.1c06204 or Chem. Rev., 2007, 107, 2411-2502
The stem cell–specific protein TRIM71 inhibits maturation and activity of the prodifferentiation miRNA let-7 via two independent molecular mechanisms RNA (IF4.942), Pub Date : 2021-07-01, DOI: 10.1261/rna.078696.121 Lucia A. Torres-Fernández, Sibylle Mitschka, Thomas Ulas, Stefan Weise, Kilian Dahm, Matthias Becker, Kristian Händler, Marc Beyer, Julia Windhausen, Joachim L. Schultze, Waldemar Kolanus
The stem cell–specific RNA-binding protein TRIM71/LIN-41 was the first identified target of the prodifferentiation and tumor suppressor miRNA let-7. TRIM71 has essential functions in embryonic development and a proposed oncogenic role in several cancer types, such as hepatocellular carcinoma. Here, we show that TRIM71 regulates let-7 expression and activity via two independent mechanisms. On the one hand, TRIM71 enhances pre-let-7 degradation through its direct interaction with LIN28 and TUT4, thereby inhibiting let-7 maturation and indirectly promoting the stabilization of let-7 targets. On the other hand, TRIM71 represses the activity of mature let-7 via its RNA-dependent interaction with the RNA-induced silencing complex (RISC) effector protein AGO2. We found that TRIM71 directly binds and stabilizes let-7 targets, suggesting that let-7 activity inhibition occurs on active RISCs. MiRNA enrichment analysis of several transcriptomic data sets from mouse embryonic stem cells and human hepatocellular carcinoma cells suggests that these let-7 regulatory mechanisms shape transcriptomic changes during developmental and oncogenic processes. Altogether, our work reveals a novel role for TRIM71 as a miRNA repressor and sheds light on a dual mechanism of let-7 regulation, uncovering a bistable switch between TRIM71 and let-7 miRNAs that regulates the balance between proliferation and differentiation.