Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Mol Cell. 2018 Jan 4;69(1):36-47.e7. doi: 10.1016/j.molcel.2017.11.021. Epub 2017 Dec 14.
Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells.
最近整合的表观基因组分析强调了功能不同的染色质状态对准确细胞功能的重要性。这些状态是如何建立和维持的是一个激烈研究的问题。在这里，我们提供了证据表明，DNA 损伤是一种意想不到的手段，可以在反复复制应激 (RS) 的区域形成保护性染色质环境。在异常叉停止时，DNA 损伤信号和伴随的 H2AX 磷酸化协调 FACT 依赖性的宏观 H2A1.2 的沉积，这是一种通过同源重组 (HR) 促进 DNA 修复的组蛋白变体。反过来，宏观 H2A1.2 促进肿瘤抑制因子和 HR 效应因子 BRCA1 在复制叉处的积累，以防止 RS 诱导的 DNA 损伤。因此，复制的原代细胞在脆弱区域稳定积累宏观 H2A1.2，而这些细胞中宏观 H2A1.2 的缺失会触发 DNA 损伤信号依赖性衰老，这是 RS 的一个标志。总的来说，我们的发现表明，反复的 DNA 损伤有助于染色质景观，以确保分裂细胞的表观基因组完整性。
