Downs J A
MRC Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK.
Oncogene. 2007 Dec 10;26(56):7765-72. doi: 10.1038/sj.onc.1210874.
Defects in the detection and repair of DNA double-strand breaks (DSBs) have been causatively linked to tumourigenesis. Moreover, inhibition of DNA damage responses (DDR) can increase the efficacy of cancer therapies that rely on generation of damaged DNA. DDR must occur within the context of chromatin, and there have been significant advances in recent years in understanding how the modulation and manipulation of chromatin contribute to this activity. One particular covalent modification of a histone variant--the phosphorylation of H2AX--has been investigated in great detail and has been shown to have important roles in DNA DSB responses and in preventing tumourigenesis. These studies are reviewed here in the context of their relevance to cancer therapy and diagnostics. In addition, there is emerging evidence for contributions by proteins involved in mediating higher order structure to DNA DSB responses. The contributions of a subset of these proteins--linker histones and high-mobility group box (HMGB) proteins--to DDR and their potential significance in tumourigenesis are discussed.
DNA双链断裂（DSB）检测与修复缺陷与肿瘤发生存在因果关联。此外，抑制DNA损伤反应（DDR）可提高依赖于产生受损DNA的癌症治疗效果。DDR必须在染色质环境中发生，近年来在理解染色质的调控与操纵如何促进这一活动方面取得了重大进展。一种组蛋白变体的特定共价修饰——H2AX的磷酸化——已得到详细研究，并已证明在DNA DSB反应及预防肿瘤发生中发挥重要作用。本文在其与癌症治疗和诊断的相关性背景下对这些研究进行综述。此外，越来越多的证据表明，参与介导高级结构的蛋白质对DNA DSB反应有贡献。本文讨论了这些蛋白质的一个子集——连接组蛋白和高迁移率族框（HMGB）蛋白——对DDR的贡献及其在肿瘤发生中的潜在意义。
