Conformational Stability Guided Recognition of Human Telomeric G-quadruplex by Human BRCA1 Protein

Human tumor suppressor protein BRCA1 recognizes noncanonical DNA structures orchestrating DNA damage repair and maintaining the genome integrity. Despite BRCA1's known preference for G-quadruplexes (G4) over double-stranded DNA, the molecular details underlying its recognition of distinct G4 conformations remain unclear. In this study, we investigated the direct interaction of human BRCA1 protein with two structurally distinct conformations of human telomeric G4 (hTeloG4) DNA - (3 + 1) hybrid and basket-type antiparallel hTeloG4. BRCA1 protein exhibited nearly 2-fold higher affinity for the hybrid hTeloG4 than the antiparallel conformation, indicating conformation-dependent recognition guided by G4 stability. Furthermore, under oxidative stress, which compromises G4 integrity due to guanine oxidation, BRCA1's binding affinity for both conformations reduced significantly. Molecular modeling and docking analyses highlighted distinct conformation-selective interaction interfaces between BRCA1 and hTeloG4. Together, these results provided insights into the conformation-guided recognition of hTeloG4 DNA by BRCA1 and suggested a potential mechanistic link between BRCA1-mediated telomere regulation.