DNA double-strand breaks induce H2Ax phosphorylation domains in a contact-dependent manner

TLDR

Efficient repair of DNA double‑strand breaks relies on a coordinated DNA damage response that includes phosphorylation of histone H2Ax (γH2Ax), which spreads beyond the break to protect chromatin and reduce rearrangements, yet the mechanisms controlling the breadth and intensity of γH2Ax domains remain unclear. The study investigates whether chromosomal contacts of a DSB site determine the extent of γH2Ax domains. DSBs that disrupt a topological border extend γH2Ax into both adjacent compartments, whereas DSBs near a border generate highly asymmetric DDR platforms with γH2Ax largely absent from one side, illustrating how DSB location influences genome integrity.

Abstract

Abstract Efficient repair of DNA double-strand breaks (DSBs) requires a coordinated DNA Damage Response (DDR), which includes phosphorylation of histone H2Ax, forming γH2Ax. This histone modification spreads beyond the DSB into neighboring chromatin, generating a DDR platform that protects against end disassociation and degradation, minimizing chromosomal rearrangements. However, mechanisms that determine the breadth and intensity of γH2Ax domains remain unclear. Here, we show that chromosomal contacts of a DSB site are the primary determinants for γH2Ax landscapes. DSBs that disrupt a topological border permit extension of γH2Ax domains into both adjacent compartments. In contrast, DSBs near a border produce highly asymmetric DDR platforms, with γH2Ax nearly absent from one broken end. Collectively, our findings lend insights into a basic DNA repair mechanism and how the precise location of a DSB may influence genome integrity.