Advertisement

ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI192225

ATR Safeguards Epithelial-to-Mesenchymal Transition by Countering R-loops and Enabling Transcription Reprogramming

Parasvi S Patel,1 Jacob P. Matson,1 Xiaojuan Ran,2 Marcello Stanzione,1 Ajinkya S. Kawale,1 Mingchao Wang,1 Sneha Saxena,1 Conrad Sander,1 Jacquelyn Curtis,1 Jessica L. Hopkins,1 Edmond Wong,1 Ryan B. Corcoran,1 Daniel A. Haber,1 Nicholas J. Dyson,1 Shyamala Maheswaran,1 and Lee Zou1

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Patel, P. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Matson, J. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Ran, X. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Stanzione, M. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Kawale, A. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Wang, M. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Saxena, S. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Sander, C. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Curtis, J. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Hopkins, J. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Wong, E. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Corcoran, R. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Haber, D. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Dyson, N. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Maheswaran, S. in: PubMed | Google Scholar

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, United States of America

2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, United States of America

Find articles by Zou, L. in: PubMed | Google Scholar

Published January 22, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI192225.
Copyright © 2026, Patel et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 22, 2026 - Version history
View PDF
Abstract

Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts, and the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increases transcription- and replication-dependent genomic instability but also disrupts transcription reprogramming. Unexpectedly, ATR inhibition elevates R-loop-associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppresses R-loops and antagonizes repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduces tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity.

Supplemental material

View Unedited blot and gel images

View

View Supplemental Information and Figures

Version history
  • Version 1 (January 22, 2026): In-Press Preview
Advertisement
Advertisement