DNA双链断裂（ DSB ）极具细胞毒性，是研究DNA损伤应答（DDR）信号网络的模式工具。 DSB应答网络是由激酶ATM驱动的，ATM一旦被DSB激活就会磷酸化在各条DDR支路中的多种蛋白。DDR牵涉广泛的蛋白动态变化，这些变化主要是由蛋白磷酸化和泛素化修饰所驱动的。Xu和Shiloh实验室对DDR和泛素化修饰的互作感兴趣。本联合研究的目标是：1、研究在DSB位点上蛋白的降解，这是DDR早期必不可少的过程。我们将用数种蛋白组学手段来鉴定在DSB位点上通过泛素-蛋白酶体系统降解的蛋白质群。 2、深入探讨泛素驱动的DDR支路的两个新因子（去泛素化蛋白酶USP11和E3连接酶UBE3A）的功能。初步数据提示这两个蛋白在DDR中发挥作用，并且是ATM的靶标。双方实验室的紧密合作将包括交换试剂和方法、联合实验以及互访交流。该研究的成果将进一步阐明DDR网络的作用机制，并在临床医学有潜在的应用价值。

Cellular DNA is highly susceptible to physical and chemical DNA damaging agents, and is constantly damaged by metabolic by-products. Maintenance of genomic stability in the face of this ongoing threat is crucial for cellular homeostasis and prevention of undue cell death or cancer. DNA lesions trigger the DNA damage response (DDR), a complex network that activates DNA repair mechanisms while temporarily modulating almost all aspects of cellular metabolism. Genetic defects in this system can lead to devastating diseases involving tissue degeneration and cancer predisposition, and are also responsible for considerable morbidity and mortality in human populations, particularly concerning premature aging and cancer. Furthermore, major cancer treatment modalities utilize DNA damaging agents, and understanding the DDR is essential for refining treatment protocols. For all these reasons, investigation of the DDR is a central field in biomedical research, with ramifications in many areas of medicine. The DNA double-strand break (DSB) is an extremely cytotoxic DNA lesion that is induced by ionizing radiations, radiomimetic chemicals and reactive oxygen species. Because the DSB so vigorously activates the DDR, it is a model DNA lesion in the study of this vital signaling network. The DSB response network is mobilized by the ATM protein kinase, which, once activated by DSBs phosphorylates a multitude of proteins in various DDR branches. The DDR involves extensive protein dynamics, which are driven largely by protein phosphorylation and ubiquitylation. The Xu and Shiloh labs are interested in the interface between the DDR and the ubiquitin family arenas. The major aims of this joint study are: 1. Investigate protein degradation at the sites of DSBs – an essential process in the early phase of the DDR. Proteomic approach will be applied in several variations to identify proteins that undergo degradation via the ubiquitin-proteasome system at DSB sites, shortly after the lesion is induced. 2. In-depth study of two new players in ubiquitin-driven branches of the DDR: the deubiquitylating protease, USP11, and the HECT-type E3 ubiquitin ligase, UBE3A (E6AP). Preliminary data indicate that both these proteins play roles in the DDR and are ATM targets. The tight collaboration between the two labs will include exchange of reagents and methods, joint experiments, and mutual visits of the PIs and members of their groups. The results of this study will add valuable information about one of the most crucial cellular signaling networks, with possible implications in several areas of clinical medicine.

蛋白磷酸化和泛素化修饰等翻译后修饰驾驭着DNA损伤应答（DDR）的信号网络。中方负责人许兴智教授和以方Shiloh教授共同探讨泛素化修饰驱动的DDR新支路。我们发现：去泛素化酶USP11通过负性调控RNF168-介导的H2AX泛素化修饰而抑制同源重组介导的DNA双链断裂（DSB）修复；蛋白磷酸酶PPM1D与蛋白激酶CK2一起协同调控RNF168介导的53BP1泛素化修饰及其向DNA损伤位点的募集；E3连接酶HERC2和去泛素化酶USP20通过协调CLASPIN的稳定性而调控复制胁迫诱导的CHK1激活；合成、筛选、鉴定了靶向DNA损伤应答的3类抗癌先导化合物（主要是喹唑啉衍生物）。这些研究成果诠释了DDR缺陷介导的基因组不稳定性和癌变的部分分子机制，为癌症诊断和治疗提供了潜在的新靶点、新策略和生物学基础。我们还先后主办/共同主办了5次DDR领域的高水平国际会议，有效促进了我国在DNA损伤修复领域的国际交流与合作，提升我国在该领域的研究水平和国际影响力。