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

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.