Torrecilla Ignacio, Oehler Judith, Ramadan Kristijan
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK
Philos Trans R Soc Lond B Biol Sci. 2017 Oct 5;372(1731). doi: 10.1098/rstb.2016.0282.
DNA double strand breaks (DSBs) are the most cytotoxic DNA lesions and, if not repaired, lead to chromosomal rearrangement, genomic instability and cell death. Cells have evolved a complex network of DNA repair and signalling molecules which promptly detect and repair DSBs, commonly known as the DNA damage response (DDR). The DDR is orchestrated by various post-translational modifications such as phosphorylation, methylation, ubiquitination or SUMOylation. As DSBs are located in complex chromatin structures, the repair of DSBs is engineered at two levels: (i) at sites of broken DNA and (ii) at chromatin structures that surround DNA lesions. Thus, DNA repair and chromatin remodelling machineries must work together to efficiently repair DSBs. Here, we summarize the current knowledge of the ubiquitin-dependent molecular unfoldase/segregase p97 (VCP in vertebrates and Cdc48 in worms and lower eukaryotes) in DSB repair. We identify p97 as an essential factor that regulates DSB repair. p97-dependent extraction of ubiquitinated substrates mediates spatio-temporal protein turnover at and around the sites of DSBs, thus orchestrating chromatin remodelling and DSB repair. As p97 is a druggable target, p97 inhibition in the context of DDR has great potential for cancer therapy, as shown for other DDR components such as PARP, ATR and CHK1.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.
DNA双链断裂（DSB）是最具细胞毒性的DNA损伤，若不修复，会导致染色体重排、基因组不稳定和细胞死亡。细胞进化出了一个由DNA修复和信号分子组成的复杂网络，能迅速检测并修复DSB，这一过程通常被称为DNA损伤反应（DDR）。DDR由各种翻译后修饰调控，如磷酸化、甲基化、泛素化或SUMO化。由于DSB位于复杂的染色质结构中，DSB的修复在两个层面进行：（i）在断裂DNA的位点；（ii）在围绕DNA损伤的染色质结构处。因此，DNA修复和染色质重塑机制必须协同工作，以有效地修复DSB。在此，我们总结了目前关于泛素依赖性分子解折叠酶/分离酶p97（在脊椎动物中为VCP，在蠕虫和低等真核生物中为Cdc48）在DSB修复中的认识。我们确定p97是调节DSB修复的关键因子。p97依赖的泛素化底物提取介导了DSB位点及其周围的时空蛋白质周转，从而协调染色质重塑和DSB修复。由于p97是一个可成药靶点，在DDR背景下抑制p97在癌症治疗方面具有巨大潜力，就像其他DDR成分如PARP、ATR和CHK1一样。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。
