ARID1A stabilises non-homologous end joining factors at DNA breaks induced by the G4 ligand pyridostatin. Sousa, Amin, et al.

Raw data for Sousa, Amin, et al., 2025
Abstract:
ARID1A is a subunit of the BAF chromatin remodelling complex that is frequently mutated in cancer. It is challenging to predict how ARID1A loss impacts cancer therapy response 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 pyridostatin when compared with isogenic controls. Sensitivity to pyridostatin was apparent in ovarian and colorectal cancer cell line models, and in vivo studies suggest that G4 ligands hold promise for treating ARID1A deficient cancers. While we find that ARID1A impacts on pyridostatin-induced transcriptional responses, we find that pyridostatin-mediated toxicity in ARID1A-deficient cells is driven by defective DNA repair of topoisomerase-induced breaks. We show that ARID1A-deficient cells are unable to efficiently accumulate non-homologous end joining proteins on chromatin following pyridostatin exposure. These data uncover a role for ARID1A in the cellular response to G4 ligands, and link remodelling to G4 ligand-induced transcriptional and DNA damage responses.

本数据集为Sousa、Amin等学者2025年发表研究的原始实验数据
摘要：
ARID1A是BAF染色质重塑复合物（BAF chromatin remodelling complex）的亚基，该复合物在癌症中存在高频突变。由于ARID1A参与多条不同的细胞信号通路，精准预测ARID1A缺失对癌症治疗应答的影响颇具挑战。G四链体（G quadruplex，G4）结合配体（如吡咯斯他丁（pyridostatin））已展现出明确的抗癌活性，但目前针对G4配体应答所涉及的细胞通路与遗传决定因子仍未完全阐明。
本研究证实，与同基因对照细胞相比，ARID1A缺失细胞对吡咯斯他丁呈现选择性敏感表型。该敏感性在卵巢癌与结直肠癌的细胞系模型中均得到验证，体内实验结果亦提示G4配体在治疗ARID1A缺失型癌症方面具有潜在应用价值。尽管本研究发现ARID1A可调控吡咯斯他丁诱导的转录应答，但ARID1A缺失细胞中吡咯斯他丁介导的细胞毒性，实则源于拓扑异构酶诱导的DNA断裂修复缺陷。进一步实验表明，经吡咯斯他丁处理后，ARID1A缺失细胞无法在染色质上有效富集非同源末端连接（non-homologous end joining，NHEJ）蛋白。本研究数据揭示了ARID1A在细胞应答G4配体过程中的关键作用，并将染色质重塑与G4配体诱导的转录应答及DNA损伤应答建立了功能关联。