Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, 2506 Speedway, Austin, TX 78712, United States.
Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, 2506 Speedway, Austin, TX 78712, United States.
Mutat Res Rev Mutat Res. 2019 Apr-Jun;780:37-47. doi: 10.1016/j.mrrev.2017.09.003. Epub 2017 Sep 23.
Preserving genome function and stability are paramount for ensuring cellular homeostasis, an imbalance in which can promote diseases including cancer. In the presence of DNA lesions, cells activate pathways referred to as the DNA damage response (DDR). As nuclear DNA is bound by histone proteins and organized into chromatin in eukaryotes, DDR pathways have evolved to sense, signal and repair DNA damage within the chromatin environment. Histone proteins, which constitute the building blocks of chromatin, are highly modified by post-translational modifications (PTMs) that regulate chromatin structure and function. An essential histone PTM involved in the DDR is histone methylation, which is regulated by histone methyltransferase (HMT) and histone demethylase (HDM) enzymes that add and remove methyl groups on lysine and arginine residues within proteins respectively. Methylated histones can alter how proteins interact with chromatin, including their ability to be bound by reader proteins that recognize these PTMs. Here, we review histone methylation in the context of the DDR, focusing on DNA double-strand breaks (DSBs), a particularly toxic lesion that can trigger genome instability and cell death. We provide a comprehensive overview of histone methylation changes that occur in response to DNA damage and how the enzymes and reader proteins of these marks orchestrate the DDR. Finally, as many epigenetic pathways including histone methylation are altered in cancer, we discuss the potential involvement of these pathways in the etiology and treatment of this disease.
维持基因组功能和稳定性对于确保细胞内环境的稳定至关重要，这种平衡的失调会导致包括癌症在内的多种疾病。当细胞内出现 DNA 损伤时，细胞会激活被称为 DNA 损伤反应（DDR）的途径。在真核生物中，由于核 DNA 被组蛋白蛋白结合并组织成染色质，DDR 途径已经进化到可以在染色质环境中感知、信号传递和修复 DNA 损伤。组蛋白蛋白是染色质的组成部分，它们高度被翻译后修饰（PTMs）修饰，这些修饰调节染色质的结构和功能。在 DDR 中涉及的一种重要的组蛋白 PTM 是组蛋白甲基化，它由组蛋白甲基转移酶（HMT）和组蛋白去甲基化酶（HDM）酶调控，这两种酶分别在赖氨酸和精氨酸残基上添加和去除甲基基团。甲基化的组蛋白可以改变蛋白质与染色质的相互作用方式，包括它们被识别这些 PTMs 的读取蛋白结合的能力。在这里，我们在 DDR 的背景下综述组蛋白甲基化，重点介绍 DNA 双链断裂（DSBs），这是一种特别有毒的损伤，可以引发基因组不稳定和细胞死亡。我们全面概述了响应 DNA 损伤而发生的组蛋白甲基化变化，以及这些标记的酶和读取蛋白如何协调 DDR。最后，由于包括组蛋白甲基化在内的许多表观遗传途径在癌症中发生改变，我们讨论了这些途径在该疾病的病因和治疗中的潜在参与。
