Nucleolin–ribosomal DNA G-quadruplex complex (NCL–rDNA G4 complex)

The Nucleolin–ribosomal DNA (rDNA) G-quadruplex (G4) complex is a regulatory assembly where the multifunctional protein nucleolin binds to G-rich sequences in rDNA that fold into four-stranded G4 structures (Hannan et al., 2013, Nature Reviews Drug Discovery). This interaction is a key regulator of RNA polymerase I (Pol I) transcription, which is responsible for synthesizing the precursor to ribosomal RNA (rRNA) (Ugrinova et al., 2018, Molecules). In cancer cells, nucleolin is often overexpressed and localized to these G4 sites to maintain the high levels of ribosome biogenesis required for rapid proliferation (Drygin et al., 2010, Cancer Research). Small molecules like CX-5461 (Pidnarulex) and CX-3543 (Quarfloxin) target this complex by stabilizing the G4 structures or displacing nucleolin, thereby inhibiting Pol I transcription and inducing nucleolar stress (Quin et al., 2016, Oncotarget). This disruption activates the DNA damage response and p53-dependent or independent apoptotic pathways, making the complex a significant target for anti-cancer therapy (Bywater et al., 2012, Cancer Cell). Beyond rDNA, nucleolin's interaction with G4s in promoter regions of oncogenes like c-MYC further underscores its importance in oncogenic signaling (Gonzalez and Hurley, 2010, Annual Review of Pharmacology and Toxicology). Targeting this specific protein-DNA interface offers a strategy to selectively impair the hyperactivated translational machinery of malignant cells while sparing normal cells to some extent.

Other names

Nucleolin–rDNA G4 complexNCL–G4 complexNucleolin–G-quadruplex interactionNucleolin–rDNA G-quadruplex complexNCL-rDNA G-quadruplex complex

Stabilization of G-quadruplex structures and displacement of nucleolin to inhibit RNA polymerase I-mediated transcription and induce nucleolar stress.