Researchers at the UNC Department of Biochemistry and Biophysics have discovered a new RNA-centric mechanism by which miRNA processing intermediates can play direct, active roles in regulating miRNA biogenesis.
These findings—published in Nature Chemical Biology—unveil that a hidden layer of regulation by which the intrinsic dynamic ensemble of miRNA processing intermediates can direct the outcome of important biological processes in response to environmental and cellular stimuli in the absence of protein factors. If these processes go awry, then disease could result. Understanding the roles of miRNAs in disease is a needed step in finding new routes to better therapeutics.
MicorRNA-21 (miR-21) is involved in the creation, progression, metastasis of cancerous tumors, and it is involved in cell survival. When researchers studied miR-21 using NMR relaxation dispersion, they found the precursor of miR-21 exists as an ensemble of dynamic conformational states, which is surprisingly sensitive to the acidity of the environment.
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They discovered that across physiological conditions, about 1–15% of the miR-21 precursor carries one additional proton, the smallest chemical modification known as protonation. With a lifetime of approximately 0.8 milliseconds, this protonated state sequesters a key residue into a new structure that substantially enhances the efficiency of processing the precursor into mature miR-21.
With these imaging techniques, scientists can now unveil transient RNA states as the hidden layers of regulation, including a fleeting riboswitch state important in controlling gene transcription. "We think these techniques add more promise for new strategies to create RNA-targeted therapeutics," concluded study leader Qi Zhang. "And that is our goal; we need better targeted therapies for many diseases including cancers."