Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7) |
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Authors: | James E Thornton Hao-Ming Chang Elena Piskounova Richard I Gregory |
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Affiliation: | 1.Stem Cell Program, Boston Children''s Hospital, Boston, Massachusetts 02115, USA;2.Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;3.Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA |
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Abstract: | The pluripotency factor Lin28 recruits a 3' terminal uridylyl transferase (TUTase) to selectively block let-7 microRNA biogenesis in undifferentiated cells. Zcchc11 (TUTase4/TUT4) was previously identified as an enzyme responsible for Lin28-mediated pre-let-7 uridylation and control of let-7 expression. Here we investigate the protein and RNA determinants for this interaction. Biochemical dissection and reconstitution assays reveal the TUTase domains necessary and sufficient for Lin28-enhanced pre-let-7 uridylation. A single C2H2-type zinc finger domain of Zcchc11 was found to be responsible for the functional interaction with Lin28. We identify Zcchc6 (TUTase7) as an alternative TUTase that functions with Lin28 in vitro, and accordingly, we find Zcchc11 and Zcchc6 redundantly control let-7 biogenesis in embryonic stem cells. Our study indicates that Lin28 uses two different TUTases to control let-7 expression and has important implications for stem cell biology as well as cancer. |
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Keywords: | Lin-28 Lin28 let-7 microRNA (miRNA) TUTase Zcchc11 Zcchc6 TUTase4 TUTase7 embryonic stem cells |
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