Making it or breaking it: DNA methylation and genome integrity.
Making it or breaking it: DNA methylation and genome integrity.
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DOI：
10.1042/ebc20200009
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发表时间：
2020-10-26
影响因子：
6.4
通讯作者：
Miller KM
中科院分区：
文献类型：
--
作者：
Sriraman A;Debnath TK;Xhemalce B;Miller KM
细胞会遇到许多外部和内部的应激因素，这些因素最终会导致DNA损伤、突变和疾病。一系列信号事件应对这些对DNA的挑战，这被称为DNA损伤反应(DDR)。DDR通过参与适当的修复途径来保持基因组的完整性，同时也协调细胞周期和/或凋亡反应。虽然DDR中的许多蛋白质成分已经确定，但对DNA的化学修饰如何影响DDR却知之甚少。本文重点介绍了DNA甲基化在维持哺乳动物细胞基因组完整性方面的研究现状。DNA甲基化是一种可逆的表观遗传标记，与DNA损伤信号、修复和复制有关。DNA甲基化位点可以触发突变，这是包括癌症在内的人类疾病的驱动因素。事实上，DNA甲基化的改变与肿瘤发生的易感性增加有关，但这是否通过对DDR、转录反应或两者的影响发生尚不完全清楚。在这里，我们还强调了目前使用的表观遗传药物作为针对DNA甲基化途径的治疗药物，并在DDR的背景下讨论它们的影响。最后，我们提出了关于DNA甲基化、转录和DDR之间的相互作用的未回答的问题，提出了这些途径在基因组完整性方面的潜在协调努力。虽然DNA甲基化对基因调控的影响已被广泛了解，但这种修饰如何直接或间接地导致基因组不稳定和突变，以及针对癌症DNA甲基化途径的潜在治疗机会仍然是活跃的研究领域。
Cells encounter a multitude of external and internal stress-causing agents that can ultimately lead to DNA damage, mutations and disease. A cascade of signaling events counters these challenges to DNA, which is termed as the DNA damage response (DDR). The DDR preserves genome integrity by engaging appropriate repair pathways, while also coordinating cell cycle and/or apoptotic responses. Although many of the protein components in the DDR are identified, how chemical modifications to DNA impact the DDR is poorly understood. This review focuses on our current understanding of DNA methylation in maintaining genome integrity in mammalian cells. DNA methylation is a reversible epigenetic mark, which has been implicated in DNA damage signaling, repair and replication. Sites of DNA methylation can trigger mutations, which are drivers of human diseases including cancer. Indeed, alterations in DNA methylation are associated with increased susceptibility to tumorigenesis but whether this occurs through effects on the DDR, transcriptional responses or both is not entirely clear. Here, we also highlight epigenetic drugs currently in use as therapeutics that target DNA methylation pathways and discuss their effects in the context of the DDR. Finally, we pose unanswered questions regarding the interplay between DNA methylation, transcription and the DDR, positing the potential coordinated efforts of these pathways in genome integrity. While the impact of DNA methylation on gene regulation is widely understood, how this modification contributes to genome instability and mutations, either directly or indirectly, and the potential therapeutic opportunities in targeting DNA methylation pathways in cancer remain active areas of investigation.