TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation

Inha Heo, Chirlmin Joo, Young Kook Kim, Minju Ha, Mi Jeong Yoon, Jun Cho, Kyu Hyeon Yeom, Jinju Han, V. Narry Kim

Research output: Contribution to journalArticlepeer-review

676 Scopus citations

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.

Original languageEnglish
Pages (from-to)696-708
Number of pages13
JournalCell
Volume138
Issue number4
DOIs
StatePublished - 21 Aug 2009

Bibliographical note

Funding Information:
We are grateful to the members of our laboratory, particularly Hyeshik Chang for helpful discussion and Ahyoung Cho and Je-Keun Rhee for technical help. We also thank Yong Joon Huh and Dr. Dong-Wook Kim for the gift of mES cells (R1) and their advice on stem cell culture; Kyung Hoon Kim and Dr. Se Won Seo for their advice on protein purification; and Drs. Guhung Jung and Seung Hwan Hong for the gift of cell lines. This work was supported by the Creative Research Initiatives Program (20090063603) through the National Research Foundation of Korea (NRF) and the BK21 Research Fellowships (I.H., C.J., Y.-K.K., J.C., K.-H.Y., and J.H.) from the Ministry of Education, Science and Technology of Korea.

Keywords

  • PROTEINS
  • RNA
  • STEMCELL

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