MAD DATA COLLECTION OF XRCC4/LIGASEIV

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。DNA双链断裂经常在细胞内遇到，作为特定重组过程的中间产物，或者可以由外部介质如电离辐射和拟辐射药物诱导。此外，代谢过程中释放的副产物也会导致双链断裂。有效修复双链断裂是至关重要的，这是通过两种不同的修复机制来实现的，其中一种是非同源末端连接修复途径。尽管存在其他修复机制，但NHEJ在高等真核生物中占主导地位，并在整个细胞周期中占主导地位。Xrcc4-DNA连接酶IV复合物是NHEJ通路的重要组成部分，负责完成连接断裂DNA末端的最后一步。解决这种人类复合体的晶体结构可以为我们提供很好的见解和启示，可以揭示这一途径的实际机制，目前尚不清楚。此外，由于缺乏适当的双链断裂修复导致细胞凋亡，通过基于结构的药物设计开发这种复合物的抑制剂可能为癌症提供一种新的治疗方法，可以与放射治疗联合使用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DNA double stranded breaks are often encountered within a cell as intermediates of particular recombination processes or can be induced by external agents such as ionizing radiation and radiomimetic drugs. In addition, double strand breaks can also occur as a result of the by-products released during metabolism. It is crucial to repair double strand breaks effectively and this is carried out by two distinct repair mechanisms, one of which is non-homologous end joining repair pathway. Although the other repair mechanism exists, NHEJ is predominant in higher eukaryotes and prevails all through out the cell cycle. Xrcc4-DNA ligase IV complex is an absolutely essential component of NHEJ pathway and is responsible for carrying out the final step of ligating the broken DNA ends. Solving the crystal structure of this human complex could provide us with great insights and revelations that could shed light on the actual mechanism of this pathway, which is currently unclear. Also, since the lack of proper double strand break repair causes apoptosis in a cell, developing inhibitors of this complex through structure-based drug design could provide a novel treatment for cancer that can be used in combination with radiation therapy.