a Departments of Cell Biology and Oncology, Faculty of Medicine and Dentistry , University of Alberta , Edmonton , Canada.
Int J Radiat Biol. 2019 Apr;95(4):382-393. doi: 10.1080/09553002.2018.1516911. Epub 2018 Sep 25.
PURPOSE: The cellular response to DNA damage occurs in the context of an organized chromatin environment in order to maintain genome integrity. Immediately after DNA damage, an array of histone modifications are induced to relieve the physical constraints of the chromatin environment, mark the site as damaged, and function as a platform for the assembly of mediator and effector proteins of DNA damage response signaling pathway. Changes in chromatin structure in the vicinity of the DNA double-strand break (DSB) facilitates the efficient initiation of the DNA damage signaling cascade. Failure of induction of DNA damage responsive histone modifications may lead to genome instability and cancer. Here we will discuss our current understanding of the DNA damage responsive histone modifications and their role in DNA repair as well as their implications for genome stability. We further discuss recent studies which highlight not only how histone modification has involved in the signaling and remodeling at the DSB but also how it influences the DNA repair pathway choice. CONCLUSIONS: Histone modifications pattern alter during the induction of DNA DSBs induction as well as during the repair and recovery phase of DNA damage response. It will be interesting to understand more precisely, how DSBs within chromatin are repaired by HR and NHEJ. The emergence of proteomic and genomic technologies in combination with advanced microscopy and imaging methods will help in better understanding the role of chromatin environment in the regulation of genome stability.
目的:为了维持基因组完整性,细胞对 DNA 损伤的反应发生在有组织的染色质环境中。在 DNA 损伤后,会立即诱导一系列组蛋白修饰,以减轻染色质环境的物理约束,将损伤部位标记为受损,并作为 DNA 损伤反应信号通路的中介和效应蛋白组装的平台。DNA 双链断裂(DSB)附近染色质结构的变化有助于高效启动 DNA 损伤信号级联反应。DNA 损伤响应组蛋白修饰的诱导失败可能导致基因组不稳定和癌症。在这里,我们将讨论我们对 DNA 损伤响应组蛋白修饰的理解及其在 DNA 修复中的作用,以及它们对基因组稳定性的影响。我们进一步讨论了最近的研究,这些研究不仅强调了组蛋白修饰如何参与 DSB 的信号转导和重塑,还强调了它如何影响 DNA 修复途径的选择。
结论:在 DNA DSBs 的诱导以及 DNA 损伤反应的修复和恢复阶段,组蛋白修饰模式会发生改变。了解更精确的 DSB 在染色质内是如何通过 HR 和 NHEJ 修复的,将是很有趣的。蛋白质组学和基因组学技术的出现,结合先进的显微镜和成像方法,将有助于更好地理解染色质环境在调节基因组稳定性中的作用。
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