ARID1A recruits non-homologous end joining factors to DNA breaks induced by G4 ligands

ARID1A is a subunit of the BAF chromatin remodelling complex that is frequently mutated in cancer. However, it is challenging to predict how ARID1A loss might impact on responses to cancer therapies because it participates in many different cellular pathways. G quadruplex (G4) binding ligands, such as pyridostatin, have shown anticancer effects, but the pathways and genetic determinants involved in the response to G4 ligands are still not fully understood. Here, we show that ARID1A deficient cells are selectively sensitive to G4 binding ligands when compared with isogenic controls. Sensitivity to G4 ligands was apparent in both ovarian clear cell and colorectal cancer cell line models, and in vivo studies suggest that G4 ligands might hold promise for treating ARID1A deficient cancers. While we find that ARID1A loss impacts on the transcriptional response to pyridostatin, we find that the influence of ARID1A on pyridostatin-mediated toxicity is driven by the DNA repair response to topoisomerase activity. Specifically, we find that ARID1A deficient cells are unable to efficiently accumulate nonhomologous end joining proteins onto chromatin following exposure to pyridostatin, providing mechanistic insights into their impaired survival. These data uncover a role for ARID1A in the cellular response to G4 ligands, and link chromatin remodelling to G4 ligand-induced DNA damage responses and genome instability.