Daxx-Dependent H3.3 Deposition Promotes Double-Strand Breaks Repair by Homologous Recombination

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• DNA double-strand breaks (DSBs) are critical DNA lesions.
• Improper DSB repair leads to genome instability and cancer.
• Homologous recombination (HR) and non-homologous end joining (NHEJ) are key DSB repair pathways.

Purpose of the Study:

• To investigate the role of the histone chaperone DAXX in DNA double-strand break (DSB) response.
• To elucidate the mechanism by which DAXX influences DSB repair pathways.

Main Methods:

• Studied human cells exposed to DNA damage.
• Analyzed DAXX phosphorylation, chromatin binding, and H3.3 deposition.
• Investigated the impact of H3.3 enrichment on 53BP1 recruitment and HR repair.

Main Results:

• DSBs induce ATM/ATR-dependent phosphorylation of DAXX.
• Phosphorylated DAXX binds chromatin and promotes H3.3 deposition near breaks.
• H3.3 enrichment at DSBs enhances 53BP1 recruitment and promotes HR repair.
• H3.3 K36 tri-methylation is critical for these processes.

Conclusions:

• DAXX plays a fundamental role in the cellular response to DSBs.
• The DAXX-H3.3 pathway is essential for promoting HR repair and maintaining genome stability.
• Mutations in DAXX or H3.3 may contribute to cancer by increasing genome instability.