Pathogenic SNPs Affect Both RNA and DNA G-Quadruplexes’ Responses to Ligands

Single nucleotide polymorphisms (SNPs) are common genetic variations that are present in over 1% of the population and can significantly modify the structures of both DNA and RNA. G-quadruplex structures (G4) are formed by the superposition of tetrads of guanines. To date, the impact of SNPs on both G4 ligands' binding efficacies and specificities has not been investigated. Here, using a bioinformatically predicted G4 and SNPs found in the α-synuclein gene as a proof-of-concept, it was demonstrated that SNPs can modulate both DNA and RNA G4s' responses to ligands. Specifically, six widely recognized ligands (Phen-DC3, PDS, 360A, RHPS4, BRACO19, and TMPyP4) were shown to differentially affect both the structure and the polymerase stalling of the different SNPs. This work highlights the importance of choosing the appropriate G4 ligand when dealing with an SNP identified in a G-rich gene.