RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell type

RNA. 2022 Mar;28(3):353-370. doi: 10.1261/rna.078976.121. Epub 2021 Dec 23.


The human terminal uridyl transferases TUT4 and TUT7 (TUT4/7) catalyze the additions of uridines at the 3' end of RNAs, including the precursors of the tumor suppressor miRNA let-7 upon recruitment by the oncoprotein LIN28A. As a consequence, let-7 family miRNAs are down-regulated. Disruption of this TUT4/7 activity inhibits tumorigenesis. Hence, targeting TUT4/7 could be a potential anticancer therapy. In this study, we investigate TUT4/7-mediated RNA regulation in two cancer cell lines by establishing catalytic knockout models. Upon TUT4/7 mutation, we observe a significant reduction in miRNA uridylation, which results in defects in cancer cell properties such as cell proliferation and migration. With the loss of TUT4/7-mediated miRNA uridylation, the uridylated miRNA variants are replaced by adenylated isomiRs. Changes in miRNA modification profiles are accompanied by deregulation of expression levels in specific cases. Unlike let-7s, most miRNAs do not depend on LIN28A for TUT4/7-mediated regulation. Additionally, we identify TUT4/7-regulated cell-type-specific miRNA clusters and deregulation in their corresponding mRNA targets. Expression levels of miR-200c-3p and miR-141-3p are regulated by TUT4/7 in a cancer cell-type-specific manner. Subsequently, BCL2, which is a well-established target of miR-200c is up-regulated. Therefore, TUT4/7 loss causes deregulation of miRNA-mRNA networks in a cell-type-specific manner. Understanding of the underlying biology of such cell-type-specific deregulation will be an important aspect of targeting TUT4/7 for potential cancer therapies.

Keywords: LIN28A; TUT4/7; cancer; isomiRs; let-7; miRNA–mRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • RNA Nucleotidyltransferases / genetics
  • RNA Nucleotidyltransferases / metabolism*
  • RNA Processing, Post-Transcriptional


  • DNA-Binding Proteins
  • MicroRNAs
  • TUT4 protein, human
  • RNA Nucleotidyltransferases
  • TUT7 protein, human