Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 16, Issue 10, Pages 1021-U33Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1676
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Funding
- The Children's Hospital Boston
- US National Institute of General Medical Sciences (NIGMS) [1R01GM086386-01A1]
- Emerald Foundation
- The March of Dimes Basil O'Conner
- The Pew Scholars Program
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Lin28 and Lin28B, two developmentally regulated RNA-binding proteins and likely proto-oncogenes, selectively inhibit the maturation of let-7 family microRNAs (miRNAs) in embryonic stem cells and certain cancer cell lines. Moreover, let-7 precursors (pre-let-7) were previously found to be terminally uridylated in a Lin28-dependent fashion. Here we identify Zcchc11 ( zinc finger, CCHC domain containing 11) as the 3' terminal uridylyl transferase (TUTase) responsible for Lin28-mediated pre-let-7 uridylation and subsequent blockade of let-7 processing in mouse embryonic stem cells. We demonstrate that Zcchc11 activity is UTP-dependent, selective for let-7 and recruited by Lin28. Furthermore, knockdown of either Zcchc11 or Lin28, or overexpression of a catalytically inactive TUTase, relieves the selective inhibition of let-7 processing and leads to the accumulation of mature let-7 miRNAs and repression of let-7 target reporter genes. Our results establish a role for Zcchc11-catalyzed pre-let-7 uridylation in the control of miRNA biogenesis.
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