ARID1A stabilizes non-homologous end joining factors at DNA breaks induced by the G4 ligand pyridostatin
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.
Authors
- Karen A. Lane (ORCID: https://orcid.org/0000-0003-0560-1502)
- Najaf Amin (ORCID: https://orcid.org/0000-0002-8944-1771)
- Jessica A. Downs (ORCID: https://orcid.org/0000-0002-6600-849X)
- Jyoti S. Choudhary (ORCID: https://orcid.org/0000-0003-0881-5477)
- Zuza Kozik (ORCID: https://orcid.org/0000-0001-6713-5776)
- Mercedes Pardo (ORCID: https://orcid.org/0000-0002-3477-9695)
- Malin Pedersen (ORCID: https://orcid.org/0000-0003-1887-733X)
- Christine Rasetti‐Escargueil (ORCID: https://orcid.org/0000-0003-0661-695X)
- Susana Banerjee (ORCID: https://orcid.org/0000-0002-8840-7934)
- Alison Harrod (ORCID: https://orcid.org/0000-0002-3977-2791)
- Manuel Stucki (ORCID: https://orcid.org/0000-0002-9974-0134)
- Kevin Joseph Harrington (ORCID: https://orcid.org/0000-0002-6014-348X)
- Katheryn Begg (ORCID: https://orcid.org/0000-0001-7711-0652)
- Susana Simoes‐Sousa (ORCID: https://orcid.org/0000-0002-1793-2926)
- Alison Ribeiro
Institutions
- Institute of Cancer Research (GB)
- University of Zurich (CH)
- Cancer Research UK (GB)
- University Hospital of Zurich (CH)
- Royal Marsden Hospital (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116277
- Citations
- 4
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
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