Chiu Li-Ya, Gong Fade, Miller Kyle M
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, 2506 Speedway, Austin, TX 78712, USA.
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, 2506 Speedway, Austin, TX 78712, USA
Philos Trans R Soc Lond B Biol Sci. 2017 Oct 5;372(1731). doi: 10.1098/rstb.2016.0286.
Genome surveillance and repair, termed the DNA damage response (DDR), functions within chromatin. Chromatin-based DDR mechanisms sustain genome and epigenome integrity, defects that can disrupt cellular homeostasis and contribute to human diseases. An important chromatin DDR pathway is acetylation signalling which is controlled by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes, which regulate acetylated lysines within proteins. Acetylated proteins, including histones, can modulate chromatin structure and provide molecular signals that are bound by acetyl-lysine binders, including bromodomain (BRD) proteins. Acetylation signalling regulates several DDR pathways, as exemplified by the preponderance of HATs, HDACs and BRD proteins that localize at DNA breaks to modify chromatin for lesion repair. Here, we explore the involvement of acetylation signalling in the DDR, focusing on the involvement of BRD proteins in promoting chromatin remodelling to repair DNA double-strand breaks. BRD proteins have widespread DDR functions including chromatin remodelling, chromatin modification and transcriptional regulation. We discuss mechanistically how BRD proteins read acetylation signals within chromatin to trigger DDR and chromatin activities to facilitate genome-epigenome maintenance. Thus, DDR pathways involving BRD proteins represent key participants in pathways that preserve genome-epigenome integrity to safeguard normal genome and cellular functions.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.
基因组监测与修复，即DNA损伤反应（DDR），在染色质中发挥作用。基于染色质的DDR机制维持基因组和表观基因组的完整性，这些缺陷会破坏细胞内稳态并导致人类疾病。一个重要的染色质DDR途径是乙酰化信号传导，它由组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）控制，这些酶调节蛋白质中的乙酰化赖氨酸。包括组蛋白在内的乙酰化蛋白质可以调节染色质结构，并提供由乙酰赖氨酸结合蛋白（包括溴结构域（BRD）蛋白）结合的分子信号。乙酰化信号传导调节多种DDR途径，例如定位在DNA断裂处的HAT、HDAC和BRD蛋白占优势，它们通过修饰染色质来修复损伤。在这里，我们探讨乙酰化信号传导在DDR中的作用，重点关注BRD蛋白在促进染色质重塑以修复DNA双链断裂中的作用。BRD蛋白具有广泛的DDR功能，包括染色质重塑、染色质修饰和转录调控。我们从机制上讨论BRD蛋白如何读取染色质中的乙酰化信号，以触发DDR和染色质活动，促进基因组-表观基因组的维持。因此，涉及BRD蛋白的DDR途径是维持基因组-表观基因组完整性以保障正常基因组和细胞功能的关键参与者。本文是主题为“DNA修复和信号传导中的染色质修饰剂和重塑剂”的特刊的一部分。
