The ubiquitin ligase human TRIM71 regulates let-7 microRNA biogenesis via modulation of Lin28B protein = Lin28B의 단백질 안정성을 조절하는 TRIM71

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The ubiquitin ligase human TRIM71 regulates let-7 microRNA biogenesis via modulation of Lin28B protein = Lin28B의 단백질 안정성을 조절하는 TRIM71
S H Lee; Sungchan Cho; M S Kim; K Choi; J Y Cho; H S Gwak; Y J Kim; H Yoo; S H Lee; J B Park; J H Kim
Bibliographic Citation
Biochimica et Biophysica Acta-Gene Regulatory Mechanisms, vol. 1839, no. 5, pp. 374-386
Publication Year
let-7 microRNA (miRNA) is implicated in various biological processes, and its downregulation essentially linked to human malignancy. Regulation of gene expression of the let-7 family is critically linked to RNA-binding proteins. For instance, Lin28B and its paralog, Lin28A, inhibit the pre-let-7 precursor from being processed to mature miRNA by recruiting terminal uridyltransferase, TUT4, which adds oligomeric U at the 3' end, suggesting that deregulation of Lin28B, together with Lin28A, may alter various biological processes through modulation of let-7 expression. Here, we showed that the Lin28B protein level is regulated via ubiquitin-mediated proteasomal degradation, and identified the ubiquitin ligase as human TRIM-NHL domain-containing TRIM71. In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination. Compared with its paralog, Lin28A, a C-terminal unique ~. 50 amino acid stretch of Lin28B is essential for TRIM71 interactions and subsequent polyubiquitination. Moreover, the N-terminal RING finger motif of TRIM71 is critical for protein-protein interactions and polyubiquitination of Lin28B, and consequent let-7 expression. Consistent with the let-7 stimulatory role of TRIM71 via Lin28B polyubiquitination, specific knockdown of TRIM71 led to downregulation of let-7 expression. Expression of one of the known let-7 targets, HMGA2, was derepressed after knockdown of TRIM71. We additionally showed that enhanced expression of let-7 is part of a feedback loop that targets TRIM71 3'UTR, which contains two conserved let-7 target sites. Our findings collectively reveal critical aspects of regulatory complexity of let-7 biogenesis at the posttranscriptional level.
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Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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