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Genetic variation and RNA structure regulate microRNA biogenesis

N. Fernández,Ross A. Cordiner,Robert S. Young,N. Hug,Sara Macias,J. Cáceres

Published 2016 in Nature Communications

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. A single variant in mir-30c-1 found in breast and gastric cancer patients leads to increased levels of mature miRNA. Here the authors show that this variant alters the RNA structure of this pri-miRNA leading to enhanced binding of SRSF3 and increased Drosha-mediated processing.

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