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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月7日

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  • Angelica Barreto-Galvez,
  • Mrunmai Niljikar,
  • Julia Elizabeth Gagliardi,
  • Carolina Plasencia Guzman,
  • Ranran Zhang,
  • Vasudha Kumar,
  • Aastha Juwarwala,
  • Archana Pradeep,
  • Ankit Saxena,
  • Cristina Montagna,
  • Priya Mittal,
  • Jeannine Gerhardt,
  • Bing Xia,
  • Jian Cao,
  • Keisuke Kataoka,
  • Adam David Durbin,
  • Jun Qi,
  • B. Hilda Ye,
  • Advaitha Madireddy

摘要

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.