Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability
DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for DNA supercoil removal, the aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from excessive TOP1cc accumulation remains unknown. Here, we identify chromatin context as an essential means to coordinate TOP1cc resolution. Through its ability to bind poly(ADP-ribose) (PAR), the histone variant macroH2A1.1 facilitates TOP1cc repair factor recruitment and lesion turnover, thereby preventing DNA damage in response to transcription-associated topological stress. The alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. We propose macroH2A1 alternative splicing as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.
Authors
- Marina Farkaš (ORCID: https://orcid.org/0000-0003-3380-7890)
- Tongwei Guan (ORCID: https://orcid.org/0000-0002-2362-5279)
- Tae-Hee Lee (ORCID: https://orcid.org/0000-0002-6263-6499)
- Qiao Chen (ORCID: https://orcid.org/0000-0003-4315-0351)
- Laura Baranello (ORCID: https://orcid.org/0000-0001-6039-1849)
- Philipp Oberdoerffer (ORCID: https://orcid.org/0000-0002-2484-1440)
- Marcus Buschbeck (ORCID: https://orcid.org/0000-0002-3218-4567)
- Vladislav Kuzin (ORCID: https://orcid.org/0000-0002-7139-1884)
- David Corujo (ORCID: https://orcid.org/0000-0001-7930-0935)
- Zhiyan Zhao
- Vijayalalitha Ramanarayanan
- Tongyu Wu
- X.E. Zhou (ORCID: https://orcid.org/0000-0003-1353-7512)
- Yubo Shi (ORCID: https://orcid.org/0000-0002-4005-2943)
Institutions
- Johns Hopkins University (US)
- University of Massachusetts Chan Medical School (US)
- University of Pittsburgh (US)
- Johns Hopkins Medicine (US)
- Karolinska Institutet (SE)
- Josep Carreras Leukaemia Research Institute (ES)
- St. John's College (US)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s41467-025-62598-w
- Citations
- 2
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Science Foundation
- University of Pennsylvania
- Johns Hopkins University
- Cancerfonden
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- National Institutes of Health
- European Regional Development Fund
- Agencia Estatal de Investigación
- Uppsala Multidisciplinary Center for Advanced Computational Science
- National Cancer Institute