TUT4 in Concert With Lin28 Suppresses microRNA Biogenesis Through pre-microRNA Uridylation

Cell. 2009 Aug 21;138(4):696-708. doi: 10.1016/j.cell.2009.08.002.

Abstract

As key regulators in cellular functions, microRNAs (miRNAs) themselves need to be tightly controlled. Lin28, a pluripotency factor, was reported to downregulate let-7 miRNA by inducing uridylation of let-7 precursor (pre-let-7). But the enzyme responsible for the uridylation remained unknown. Here we identify a noncanonical poly (A) polymerase, TUTase4 (TUT4), as the uridylyl transferase for pre-let-7. Lin28 recruits TUT4 to pre-let-7 by recognizing a tetra-nucleotide sequence motif (GGAG) in the terminal loop. TUT4 in turn adds an oligouridine tail to the pre-let-7, which blocks Dicer processing. Other miRNAs with the same sequence motif (miR-107, -143, and -200c) are regulated through the same mechanism. Knockdown of TUT4 and Lin28 reduces the level of stem cell markers, suggesting that they are required for stem cell maintenance. This study uncovers the role of TUT4 and Lin28 as specific suppressors of miRNA biogenesis, which has implications for stem cell research and cancer biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Embryonic Stem Cells / cytology*
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • MicroRNAs / metabolism*
  • Polynucleotide Adenylyltransferase / metabolism*
  • Uridine / metabolism*

Substances

  • MicroRNAs
  • mirnlet7 microRNA, human
  • Polynucleotide Adenylyltransferase
  • Uridine