表观遗传调控：基于染色质环境的DNA双链断裂修复

DNA双链断裂（DNA double-strand breaks, DSBs）是威胁基因组完整性和细胞存活的最有害的DNA损伤类型。同源重组（homologous recombination，HR）和非同源末端连接（non-homologous end joining，NHEJ）是修复DNA双链断裂的两种主要途径。DSB修复涉及到损伤部位修复蛋白的募集和染色质结构的改变。在DNA双链断裂诱导下，染色质结构的动态变化在时间和空间上受到严格调控，进而对DNA双链断裂修复过程进行精细调节。特定的染色质修饰形成利于修复的染色质状态，有助于DNA双链断裂修复机器的招募、修复途径的选择和DNA损伤检查点的活化；其中修复途径的选择对于基因组稳定性至关重要。修复不当或失败可导致基因组不稳定性，甚至促进肿瘤的发生。本文综述了染色质结构和染色质修饰的动态变化在DSB修复中的重要作用。此外，文章还总结了在癌症治疗中靶向关键染色质调控因子在基因组稳定性维持、肿瘤发生发展以及潜在临床应用价值等方面的进展。

Epigenetic Regulation: Repair of DNA Double-Strand Breaks in Chromatin Context

DNA double-strand breaks (DSBs) is the most deleterious DNA lesion that threatens genomic integrity and cell survival. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two major repair pathways. The repair of DSBs involves both concentration of DNA repair proteins at the site of damage and alterations of chromatin structure. Dynamic changes of chromatin architecture surrounding the DSBs are spatially and temporally regulated, so as to elaborately regulate DSB repair. Specific chromatin modifications develop a repair permissive chromatin state, which directly contributes to the access and assembly of DSB repair machinery, channels repair pathway choice and controls DNA damage checkpoints. Notably, repair pathway choice is critical to genome stability. Inappropriate repair or repair failure will lead to genome instability and even contribute to tumorigenesis. In this review, we summarize the important roles of chromatin structure and dynamic changes of chromatin modifications in DSB repair. Also, we highlight the concept of targeting chromatin regulators in response to genotoxic stress for cancer treatment, and how this can provide significant opportunities for DNA damage-based therapies in the future.