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

## TL;DR

This study shows that EP300 deficiency causes replication problems in cancer cells, leading to genomic instability and features similar to BRCA-deficient cancers.

## Contribution

The study reveals a novel role for EP300 in replication fork protection and links its deficiency to BRCA2 downregulation and genomic instability.

## Key findings

- EP300 loss causes elevated replication origin firing and genomic instability.
- EP300 deficiency leads to defective replication fork protection and single-stranded DNA gaps.
- BRCA2 expression is reduced in EP300-mutated cells, mimicking BRCA-deficient cancer features.

## Abstract

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.

Loss-of-function mutations in EP300/KAT3B and CBP/KAT3A have been implicated in the pathogenesis of cancer. Here, the authors reveal that the EP300 protein has a role in mediating replication fork protection at sites of replication stalling and show that EP300-mutated cells recapitulate features of BRCA-deficient cancers.