Work

ARID1A stabilizes non-homologous end joining factors at DNA breaks induced by the G4 ligand pyridostatin

Year: 2025

Type: article

Abstract: ARID1A, a subunit of the BAF chromatin remodeler, is frequently mutated in cancer. Predicting how ARID1A loss impacts cancer therapy response is challenging because it influences many cellular pathways. G quadruplex (G4) binding ligands, such as pyridostatin, show anticancer effects, but the genetic determinants influencing the response to G4 ligands are not fully understood. Here, we show that ARID1A-deficient cells are selectively sensitive to pyridostatin compared to isogenic controls. This was apparent in ovarian and colorectal cancer cell line models, and in vivo studies suggest that G4 ligands hold promise for ARID1A-deficient cancers. While ARID1A modulates pyridostatin-induced transcriptional responses, we show that toxicity in ARID1A-deficient cells arises from the defective repair of topoisomerase-induced breaks. Notably, these cells fail 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, linking remodeling to G4 ligand-induced responses.

Source: Cell Reports

DOI: 10.1016/j.celrep.2025.116277

Authors: Susana Simões-Sousa, Noa Amin, Karen A. Lane, Alison Harrod, Malin Pedersen, Mercedes Pardo, Christine Rasetti-Escargueil, Zuzanna Kozik, Katheryn A.G. Begg, Alison Ribeiro, Susana Banerjee, Manuel Stucki, Kevin J. Harrington, Jyoti S. Choudhary, Jessica A. Downs

Institutions: Institute of Cancer Research, University of Zurich, University Hospital Zurich, Royal Marsden Hospital

Language: English

Topic: Chromatin Remodeling and Cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,620

Funders: National Science Foundation, Wellcome Trust, Cancer Research UK, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Helmut Horten Stiftung, Medical Research Council, Biotechnology and Biological Sciences Research Council

Awards: Deciphering immune signalling changes and the influence of irradiation in SWI/SNF deficient cells, Unravelling SWI/SNF ARID1A/B paralogs function at sequence resolution, Energetics and excited state dynamics of new light-emitting inorganic materials, G4785333599, Geological pattern recognition and geodynamical analysis using 3D seismic data, Exploring the cellular response to DNA double-strand breaks in special chromatin environments, G699262904, G7373044524, G8690818240, Extending the PRIDE database ecosystem: PRIDE-Controlled Access (PRIDE-CA) and the PRIDE-Knowledgebase (PRIDE-KB), Exploring novel functions of the tumor suppressor NBS1 in the maintenance of genome stability

OpenAlex ID: W4414154773

FWCI: 1.789

Cites: 48

Cited by: 7

Related to: 10