Abstract
The pluripotency-promoting proteins Lin28a and Lin28b act as post-transcriptional repressors of let-7 miRNA biogenesis in undifferentiated embryonic stem cells. The levels of mature let-7a differ substantially in cells lacking Lin28 expression, indicating the existence of additional mechanism(s) of post-transcriptional regulation. Here, we present evidence supporting a role for heteronuclear ribonucleoprotein A1 (hnRNP A1) as a negative regulator of let-7a. HnRNP A1 binds the conserved terminal loop of pri-let-7a-1 and inhibits its processing by Drosha. Levels of mature let-7a negatively correlate with hnRNP A1 levels in somatic cell lines. Furthermore, hnRNP A1 depletion increased pri-let-7a-1 processing by cell extracts, whereas its ectopic expression decreased let-7a production in vivo. Finally, hnRNP A1 binding to let-7a interferes with the binding of KSRP, which is known to promote let-7a biogenesis. We propose that hnRNP A1 and KSRP have antagonistic roles in the post-transcriptional regulation of let-7a expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Binding, Competitive
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Cell Line, Tumor
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DNA Footprinting
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Gene Expression Regulation, Neoplastic
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Green Fluorescent Proteins / metabolism
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Heterogeneous Nuclear Ribonucleoprotein A1
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
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Humans
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MicroRNAs / biosynthesis*
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MicroRNAs / chemistry
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MicroRNAs / genetics
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Models, Biological
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Molecular Sequence Data
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Nucleic Acid Conformation
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Protein Binding
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RNA Processing, Post-Transcriptional
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Recombinant Fusion Proteins / metabolism
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Ribonuclease III / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
Substances
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Heterogeneous Nuclear Ribonucleoprotein A1
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B
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KHSRP protein, human
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MicroRNAs
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RNA-Binding Proteins
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Recombinant Fusion Proteins
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Trans-Activators
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mirnlet7 microRNA, human
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Green Fluorescent Proteins
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DROSHA protein, human
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Ribonuclease III