EP300 deficiency leads to chronic replication stress mediated by defective replication fork protection
Mutations in the global transcriptional activator EP300/KAT3B are being reported in aggressive malignancies. However, the mechanistic contribution of EP300 dysregulation to cancer is currently unknown. While EP300 has been implicated in regulating cell cycle and DNA replication, the role of EP300 in maintaining replication fork integrity has not been studied. Here, using EP300-mutated adult T-cell leukemia/lymphoma cells and an EP300-selective degrader, we reveal that EP300 loss leads to pronounced dysregulations in DNA replication dynamics and persistent genomic instability. Aberrant DNA replication in EP300-mutated cells is characterized by elevated replication origin firing due to replisome pausing. EP300 deficiency results in a prominent defect in fork protection resulting in the accumulation of single-stranded DNA gaps. Importantly, we find that the loss of EP300 results in decreased expression of BRCA2 protein leading to sensitivity to treatments that are cytotoxic to BRCA-deficient cancers. Overall, we demonstrate that EP300-mutated cells recapitulate features of BRCA-deficient cancers.
Authors
- Julia Gagliardi
- Jeannine Gerhardt (ORCID: https://orcid.org/0000-0002-6672-3012)
- Ranran Zhang (ORCID: https://orcid.org/0000-0001-5698-1950)
- Keisuke Kataoka (ORCID: https://orcid.org/0000-0002-8263-9902)
- Jian Cao (ORCID: https://orcid.org/0000-0003-3424-6802)
- Priya Mittal (ORCID: https://orcid.org/0000-0001-6921-3934)
- Mrunmai Niljikar (ORCID: https://orcid.org/0009-0004-3438-7378)
- Angelica Barreto-Galvez (ORCID: https://orcid.org/0000-0002-3731-6741)
- Archana Pradeep
- Ankit Saxena (ORCID: https://orcid.org/0000-0001-5305-3681)
- Vasudha Kumar
- Adam D. Durbin (ORCID: https://orcid.org/0000-0002-5472-9847)
- Aastha Juwarwala (ORCID: https://orcid.org/0009-0006-8397-9913)
- Jun Qi (ORCID: https://orcid.org/0000-0002-1461-3356)
- Cristina Montagna (ORCID: https://orcid.org/0000-0003-2343-5851)
- B. Hilda Ye (ORCID: https://orcid.org/0000-0002-2281-422X)
- Advaitha Madireddy (ORCID: https://orcid.org/0000-0002-4730-5325)
- Bing Xia (ORCID: https://orcid.org/0000-0003-3259-6139)
- Carolina Plasencia Guzman
Institutions
- Rutgers, The State University of New Jersey (US)
- Albert Einstein College of Medicine (US)
- St. Jude Children's Research Hospital (US)
- Harvard University (US)
- Cornell University (US)
- Johnson University (US)
- Dana-Farber Cancer Institute (US)
- Weill Cornell Medicine (US)
- Rutgers Cancer Institute (US)
- UC Davis Comprehensive Cancer Center
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-07
- DOI
- https://doi.org/10.1038/s41467-025-67171-z
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00