The stem cell-specific protein TRIM71 inhibits maturation and activity of the pro-differentiation miRNA let-7 via two independent molecular mechanisms.
The stem cell-specific RNA-binding protein TRIM71/LIN-41 was the first identified target of the pro-differentiation 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 datasets 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.
['Torres Fernández|Lucia A|LA|http://orcid.org/0000-0002-8890-6258', 'Mitschka|Sibylle|S|', 'Ulas|Thomas|T|', 'Weise|Stefan|S|', 'Dahm|Kilian|K|', 'Becker|Matthias|M|', 'Händler|Kristian|K|', 'Beyer|Marc|M|', 'Windhausen|Julia|J|', 'Schultze|Joachim L|JL|http://orcid.org/0000-0003-2812-9853', 'Kolanus|Waldemar|W|http://orcid.org/0000-0003-1325-9444']
TRIM71/LIN-41 RNA-binding protein (RBP) let-7 miRNA family miRNA pathway stem cell and cancer biology