An international research team has used an integrated structural biological approach to elucidate the maturation of a cancer-causing microRNA in gene regulation as presented in Nature Communications.
MicroRNAs (miRNAs) are a class of molecules consisting of short RNA sequences that inhibit the formation of certain proteins by destroying the corresponding RNA blueprint.
Cancer-causing miRNAs, so-called oncomiRs, also function according to this principle and inhibit the production of proteins that protect the cell against uncontrolled growth. "Thus, an increased presence of these molecules in cells leads to the development of cancer in the long term," said the senior author. "However, some molecular mechanisms of miRNA maturation in the cell remain elusive."
Usually, before a miRNA can act in the cell, it undergoes several maturation steps and develops from a so-called primary pri-miRNA via a precursor stage (pre-miRNA) to a mature miRNA. In the current study, the researchers investigated the maturation of a specific pri-miRNA.
"Our research focused on the maturation of miRNA-18a, which has been associated with colon, breast, and esophageal cancer," said the author. "To elucidate how its maturation is controlled, we had to combine different procedures. Nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography, small-angle X-ray scattering analyses as well as biochemical experiments were used."
Using this combination approach, the authors were able to show exactly how a specific RNA binding protein (hnRNP A1) recognizes pri-miRNA-18a and changes its structure in such a way that it develops into mature miRNA-18a.
Authors show that hnRNP A1 forms a 1:1 complex with pri-mir-18a where both RNA recognition motifs (RRMs) bind to cognate RNA sequence motifs in the terminal loop of pri-mir-18a. Terminal loop binding induces an allosteric destabilization of base-pairing in the pri-mir-18a stem that promotes its downstream processing.
The researchers assume that the mechanism can also be transferred to other miRNAs. "In the long term, understanding the processes might help us to develop new therapy options - for example to treat cancer," said the author. "Only if we understand how biology works we can intervene in a targeted manner."
Mechanism of miRNA maturation!
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