The SMARCA4 subunit of the SWI/SNF complex prevents genome instability at G quadruplexes.

G-quadruplex (G4) structures are secondary structures that can form in guanine-rich single stranded DNA sequences. These play important roles in biological processes such as regulation of gene expression but can also pose challenges to DNA replication and lead to genome instability. The SMARCA4 (BRG1) subunit of the SWI/SNF chromatin remodelling complexes has been identified as a G4 binding protein, and evidence suggests that this interaction can promote SWI/SNF-dependent gene expression. SMARCA4 is frequently misregulated in cancer, where genome instability is common, but whether there is an impact of SMARCA4 on G4 stability was not known. Here, we show that SMARCA4 prevents genome instability at G4s. Mapping unrepaired DNA breaks reveals that these preferentially co-localise with G4 forming structures in SMARCA4-deficient cells. Moreover, using whole genome sequencing approaches, we find that misrepair events in SMARCA4-deficient cells are more likely to map to G4 forming sequences. Consistent with this, SMARCA4-deficient cells show sensitivity to the G4 ligand pyridostatin and defective pyridostatin-induced DNA damage responses. Notably, analysis of cancer patient data shows that SMARCA4-deficient samples have an increased proportion of G4-associated mutations when compared with SMARCA4-proficient samples. These findings suggest that SMARCA4 plays a crucial role in maintaining stability at G4 motifs. This insight provides valuable information about the functional significance of G4 structures and their interaction with SMARCA4, particularly in the context of cancer.