The role of a G-quadruplex structure in mediating the interactions of miR-1249-3p with the 3-UTR of the HNRNPK mRNA

Heterogenous nuclear riboprotein K (hnRNP K) is an important regulator of multiple signaling pathways involved in DNA repair and function whose expression has been found to be mis-regulated in many cancers and neurological diseases. The expression regulation of hnRNP K is not fully understood however it has been shown that the microRNA miR-1249-3p targets its mRNA 3-untranslated region (UTR), regulating its translation. In this study we identified a guanosine-rich sequence in the HNRNPK 3-UTR within the miR-1249-3p binding site that has the potential to form a G-quadruplex (GQ) structure. By using various biophysical methods, we show that this sequence forms a parallel GQ structure which modulates the binding of miR-1249-3p to HNRNPK 3-UTR in vitro. Additionally, using luciferase reporter assays, we determined that this GQ structure affects the hnRNP K protein expression, suggesting modulation of the binding interaction of miR-1249-3p to the 3-UTR of HNRNPK. This HNRNPK mRNA GQ-miR binding axis is an unexplored mechanism of regulation, offering a novel therapeutic target for diseases caused by abnormal hnRNP K expression.