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EP300 deficiency leads to chronic replication stress mediated by defective replication fork protection

Angelica Barreto-Galvez1, Mrunmai Niljikar1, Julia Elizabeth Gagliardi1

  • 1Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

Nature Communications
|December 7, 2025
PubMed

Insights

Loss of EP300 (also known as KAT3B) in cancer cells disrupts DNA replication, causing genomic instability and sensitivity to BRCA-deficient cancer treatments. This highlights EP300

Area of Science:

  • Molecular Biology
  • Cancer Genomics
  • DNA Replication

Background:

  • Mutations in EP300/KAT3B are linked to aggressive cancers, but the underlying mechanisms remain unclear.
  • EP300 is known to regulate cell cycle and DNA replication, yet its role in maintaining replication fork integrity is unstudied.

Purpose of the Study:

  • To investigate the mechanistic contribution of EP300 dysregulation to cancer.
  • To explore the role of EP300 in maintaining DNA replication fork integrity and its impact on genomic stability.

Main Methods:

  • Utilized EP300-mutated adult T-cell leukemia/lymphoma cell lines.
  • Employed an EP300-selective degrader to study the effects of EP300 loss.
  • Analyzed DNA replication dynamics, replisome pausing, fork protection, and single-stranded DNA gap accumulation.

Main Results:

  • EP300 loss induces significant dysregulation in DNA replication dynamics and persistent genomic instability.
  • Cells exhibit aberrant DNA replication with increased origin firing due to replisome pausing and impaired fork protection.
  • EP300 deficiency leads to decreased BRCA2 expression, conferring sensitivity to treatments targeting BRCA-deficient cancers.

Conclusions:

  • EP300 loss disrupts DNA replication fork integrity, leading to genomic instability in cancer cells.
  • EP300-mutated cells exhibit characteristics similar to BRCA-deficient cancers, including sensitivity to specific therapies.
  • This study reveals EP300 as a critical factor in maintaining genomic stability and suggests therapeutic vulnerabilities in EP300-mutated malignancies.

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