Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, 43210, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Nat Commun. 2020 Jun 22;11(1):3158. doi: 10.1038/s41467-020-16926-x.
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.
高效修复 DNA 双链断裂 (DSB) 需要协调的 DNA 损伤反应 (DDR)，包括组蛋白 H2Ax 的磷酸化，形成 γH2Ax。这种组蛋白修饰会在 DSB 之外扩散到相邻的染色质中，形成 DDR 平台，防止末端解离和降解，最大限度地减少染色体重排。然而，决定 γH2Ax 结构域的广度和强度的机制尚不清楚。在这里，我们表明 DSB 位点的染色体接触是 γH2Ax 景观的主要决定因素。破坏拓扑边界的 DSB 允许 γH2Ax 结构域延伸到两个相邻的隔室中。相比之下，边界附近的 DSB 会产生高度不对称的 DDR 平台，其中一个断裂端几乎没有 γH2Ax。总的来说，我们的发现为基本的 DNA 修复机制以及 DSB 的精确位置如何影响基因组完整性提供了新的见解。
