Neuroblastoma RAS viral oncogene homolog mRNA G-quadruplex (NRAS mRNA G4)

The NRAS mRNA G-quadruplex is a non-canonical, four-stranded secondary structure located within the 5' untranslated region (UTR) of the NRAS (Neuroblastoma RAS viral oncogene homolog) transcript. This structure is formed by guanine-rich sequences that fold into a stable arrangement through Hoogsteen hydrogen bonding, serving as a natural cis-regulatory element that modulates NRAS protein synthesis. Biologically, the G-quadruplex acts as a translational repressor by obstructing the scanning of the 43S ribosomal pre-initiation complex along the mRNA leader sequence. In many human cancers, such as melanoma and various leukemias, NRAS is constitutively activated or overexpressed, making it a primary driver of uncontrolled cell proliferation and survival. Because the NRAS protein has historically been difficult to target directly with small molecules, the NRAS mRNA G-quadruplex has emerged as a promising alternative therapeutic target. Small-molecule ligands designed to stabilize this structure can effectively downregulate NRAS expression at the translational level, leading to reduced oncogenic signaling and the induction of apoptosis in cancer cells.

Other names

NRAS 5'-UTR G-quadruplexNRAS rG4NRAS mRNA G-quadruplex structureNRAS G-quadruplex

Small-molecule ligands bind to and stabilize the G-quadruplex structure within the 5' untranslated region (UTR) of the NRAS mRNA, creating a physical barrier that impedes ribosomal scanning and inhibits translation initiation, or alternatively, induces targeted mRNA degradation through reactive oxygen species (ROS) generation in photodynamic therapy.