biostudies-literatureSu AMNorthwest A and F UniversityNational Natural Science Foundation of China110897https://www.ebi.ac.uk/biostudies/studies/S-EPMC12704285biostudies-literatureUnknown301(12)Noncanonical four-stranded DNA structures known as G-quadruplexes (G4s) play crucial roles in gene regulation and have recently been identified as hotspots for single-nucleotide variations (SNVs). In the cMyc proto-oncogene promoter, the Pu27 G4 element serves as a key transcriptional switch, yet its susceptibility to SNVs and the resulting molecular consequences remain unclear. Here, we systematically analyze SNVs in the cMyc promoter G4 using the dbSNP database and identify 17 mutation sites distributed across its 27-nt sequence, indicating a high mutation frequency. Biophysical studies reveal that SNVs in loop regions primarily enhance G4 stability by introducing additional hydrogen bonds and π-π interactions while maintaining its parallel topology. In contrast, SNVs within G-runs destaThe Journal of biological chemistryMutational landscape of the G-quadruplex DNA in cMyc proto-oncogene promoter: Insights into the structural polymorphism and transcriptional regulation.PMC1270428532071225A1080525005Chen QYWang DHou XMSu AMYu XYLu WJfalseMutational landscape of the G-quadruplex DNA in cMyc proto-oncogene promoter: Insights into the structural polymorphism and transcriptional regulation.Noncanonical four-stranded DNA structures known as G-quadruplexes (G4s) play crucial roles in gene regulation and have recently been identified as hotspots for single-nucleotide variations (SNVs). In the cMyc proto-oncogene promoter, the Pu27 G4 element serves as a key transcriptional switch, yet its susceptibility to SNVs and the resulting molecular consequences remain unclear. Here, we systematically analyze SNVs in the cMyc promoter G4 using the dbSNP database and identify 17 mutation sites distributed across its 27-nt sequence, indicating a high mutation frequency. Biophysical studies reveal that SNVs in loop regions primarily enhance G4 stability by introducing additional hydrogen bonds and π-π interactions while maintaining its parallel topology. In contrast, SNVs within G-runs desta2025-01-01T00:00:00Z2025 Nov2026-06-06T04:18:13.114Z2026-05-25T03:11:58.506ZS-EPMC127042854119773510.1016/j.jbc.2025.110897