The expanding repertoire of G4 DNA structures

•Interrupted or truncated G-runs are frequently tolerated in G4-forming sequences.•G4s with defects are as responsive to quadruplex-targeted ligands as perfect G4s.•Defective G4 motifs exhibit non-random distribution in the human genome.

The definition of DNA and RNA G-quadruplexes (G4s) has recently been broadened to include structures with certain defects: bulges, G-vacancies or mismatches. Despite the striking progress in computational methods for assessing G4 folding propensity, predicting G4s with defects remains problematic, reflecting the enhanced sequential diversity of these motifs. “Imperfect” G4 motifs, i.e., those containing interrupted or truncated G-runs, are typically omitted from genomic analyses. We report here studies of G4s with defects and compare these structures with classical (“perfect”) quadruplexes. Thermal stabilities and ligand interactions are also discussed. We exploited a simple in-house computational tool for mining putative G4s with defects in the human genome. The obtained profiles of the genomic distribution of imperfect G4 motifs were analyzed. Collectively, our findings suggest that, similar to classical G4s, imperfect G4s could be considered as potential regulatory elements, pathology biomarkers and therapeutic targets.