Acetylation Reader Proteins: Linking Acetylation Signaling to Genome Maintenance and Cancer.
Acetylation Reader Proteins: Linking Acetylation Signaling to Genome Maintenance and Cancer.
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DOI：
10.1371/journal.pgen.1006272
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发表时间：
2016-09
期刊：
影响因子：
4.5
通讯作者：
Miller KM
中科院分区：
文献类型：
--
作者：
Gong F;Chiu LY;Miller KM
基于染色质的DNA损伤反应（DDR）途径是预防癌症中普遍存在的基因组和表观基因组不稳定性的基础。组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）催化赖氨酸残基上乙酰基的添加和去除，这是对DDR重要的翻译后修饰。乙酰化可以通过为含有乙酰基-赖氨酸识别结构域（包括溴结构域（BRD））的阅读器蛋白提供结合信号来改变染色质结构以及功能。乙酰化动力学在DNA损伤后发生，部分地调节染色质和BRD蛋白质的相互作用，其介导关键的DDR活性。在癌症中，DDR和乙酰化途径经常发生突变或异常表达。靶向表观遗传调节剂（包括HAT、HDAC和BRD蛋白）的DNA损伤剂和药物被用于或正在开发用于治疗癌症。在这里，我们讨论了组蛋白乙酰化途径，重点是乙酰化阅读器蛋白，促进基因组稳定性和DDR。我们分析了乙酰化信号如何在癌症及其治疗的背景下影响DDR。理解表观遗传调节因子、DDR和染色质之间的关系对于获得基因组和表观基因组维持途径的机制理解、可以用于靶向乙酰化信号传导的信息和/或DDR以治疗疾病（包括癌症）是不可或缺的。
Chromatin-based DNA damage response (DDR) pathways are fundamental for preventing genome and epigenome instability, which are prevalent in cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the addition and removal of acetyl groups on lysine residues, a post-translational modification important for the DDR. Acetylation can alter chromatin structure as well as function by providing binding signals for reader proteins containing acetyl-lysine recognition domains, including the bromodomain (BRD). Acetylation dynamics occur upon DNA damage in part to regulate chromatin and BRD protein interactions that mediate key DDR activities. In cancer, DDR and acetylation pathways are often mutated or abnormally expressed. DNA damaging agents and drugs targeting epigenetic regulators, including HATs, HDACs, and BRD proteins, are used or are being developed to treat cancer. Here, we discuss how histone acetylation pathways, with a focus on acetylation reader proteins, promote genome stability and the DDR. We analyze how acetylation signaling impacts the DDR in the context of cancer and its treatments. Understanding the relationship between epigenetic regulators, the DDR, and chromatin is integral for obtaining a mechanistic understanding of genome and epigenome maintenance pathways, information that can be leveraged for targeting acetylation signaling, and/or the DDR to treat diseases, including cancer.
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