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

## TL;DR

This study shows how the DAXX protein helps repair DNA breaks by placing a special histone variant, H3.3, at the site of damage, which supports a key DNA repair process.

## Contribution

The study reveals a new role for DAXX in promoting homologous recombination repair of DNA breaks through H3.3 deposition.

## Key findings

- DAXX is phosphorylated at serine 424 and 712 in response to DNA breaks, leading to chromatin binding.
- DAXX promotes H3.3 deposition near DNA breaks, which aids in recruiting 53BP1 and repairing breaks via homologous recombination.
- H3.3 modifications like K36 tri-methylation are crucial for this repair process and may contribute to genome instability in cancer.

## Abstract

DNA double-strand breaks (DSBs) can be induced by cellular byproducts or genotoxic agents. Improper processing of these lesions leads to increased genome instability, which constitutes a hallmark of pathological conditions and fuels carcinogenesis. DSBs are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) and the proper balance between these two pathways is finely modulated by specific molecular events. Here, we report that the histone chaperone DAXX plays a fundamental role in the response to DSBs. Indeed, in human cells, DSBs induce ATM/ATR-dependent phosphorylation of DAXX on serine 424 and 712 and promote its binding to chromatin and the deposition of the histone variant H3.3 in proximity to DNA breaks. Enrichment of H3.3 at DSBs promotes 53BP1 recruitment to these lesions and the repair of DNA breaks by HR pathways. Moreover, H3.3-specific post translational modifications, particularly K36 tri-methylation, play a key role in these processes. Altogether, these findings indicate that DAXX and H3.3 mutations may contribute to tumorigenesis-enhancing genome instability.