Dynamic interaction of BRCA2 with telomeric G-quadruplexes underlies telomere replication homeostasis

Abstract BRCA2-deficient cells undergo telomere shortening upon collapse of stalled replication forks, particularly during lagging-strand telomere synthesis. The molecular mechanism underlying fork collapse remains unclear. Here we find that the BRCA2 C-terminus, which includes an OB-fold, specifically interacts with G-quadruplex (G4) structures generated during lagging-strand telomere replication. We demonstrate that BRCA2 associates with G-triplex (G3)-derived intermediates using electrophoretic mobility shift assay and single-molecule FRET. These G3 intermediates form during direct interconversion between parallel and non-parallel G4 structures. Intriguingly, MRE11 nuclease can resect G4-forming telomere sequences, a function that is inhibited by BRCA2. BRCA2 depletion consistently resulted in increased telomeric damage, which was relieved by MRE11 knockdown. These data suggest that BRCA2 interaction with telomeric G4 prevents MRE11-mediated resection. The specific interaction between BRCA2 and G4 therefore contributes to telomere stability and genome integrity.