Genetic variation and RNA structure regulate microRNA biogenesis

Noemi Fernandez, Ross A. Cordiner, Robert S. Young, Nele Hug, Sara Macias and Javier F. Cáceres ()
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Noemi Fernandez: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Genome Regulation Section, Western General Hospital, University of Edinburgh
Ross A. Cordiner: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Genome Regulation Section, Western General Hospital, University of Edinburgh
Robert S. Young: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Genome Regulation Section, Western General Hospital, University of Edinburgh
Nele Hug: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Genome Regulation Section, Western General Hospital, University of Edinburgh
Sara Macias: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Genome Regulation Section, Western General Hospital, University of Edinburgh
Javier F. Cáceres: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Genome Regulation Section, Western General Hospital, University of Edinburgh

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract MiRNA biogenesis is highly regulated at the post-transcriptional level; however, the role of sequence and secondary RNA structure in this process has not been extensively studied. A single G to A substitution present in the terminal loop of pri-mir-30c-1 in breast and gastric cancer patients had been previously described to result in increased levels of mature miRNA. Here, we report that this genetic variant directly affects Drosha-mediated processing of pri-mir-30c-1 in vitro and in cultured cells. Structural analysis of this variant revealed an altered RNA structure that facilitates the interaction with SRSF3, an SR protein family member that promotes pri-miRNA processing. Our results are compatible with a model whereby a genetic variant in pri-mir-30c-1 leads to a secondary RNA structure rearrangement that facilitates binding of SRSF3 resulting in increased levels of miR-30c. These data highlight that primary sequence determinants and RNA structure are key regulators of miRNA biogenesis.

Date: 2017
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DOI: 10.1038/ncomms15114

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