Understanding the role of RAD51C complexes in recombination and repair

项目摘要 修复DNA断裂的功能性机制是维持基因组完整性所必需的， 防止肿瘤发生。为了深入了解复杂的DNA断裂修复机制， 在哺乳动物细胞中，识别每个步骤所需的新因子是至关重要的。 修复事件。同样，我们需要确定已知的DNA断裂修复蛋白的作用，如 RAD51旁系同源物，因为这些蛋白质中的突变与癌症增加有关， 癌症患者在接受细胞毒性治疗后的风险和生存率降低。上一次，我们发现了两个 RAD51旁系同源物、RAD51C和XRCC3作为Holliday连接的基本组成部分， resolvasome是一种在DNA断裂修复过程中分离连锁染色体所需的复合物。这 这一发现不仅表明了RAD51C和XRCC3在重组后期的新作用， 也在处理停滞的复制分叉中。此外，我们的研究还表明， RAD51C与ERCC1和RECQ解旋酶的复合物，这两者对于 处理重组中间体和停滞的复制叉。我们的目标是定义这些 RAD51C复合物在重组修复中的独特功能，可以解释它们在 基因组的维持和发展。 本研究的主要目的是：（1）在大肠杆菌中筛选和鉴定与RAD51C相互作用的新蛋白。 重组修复(2)RAD51C复合物与细胞凋亡的功能关系分析 ERCC1。(3)RAD51C复合物与细胞凋亡功能关系的生化分析 RECQ蛋白。项目叙述 我们的研究目标是了解修复受损DNA的复杂机制，因为损失 基因组的完整性会导致细胞转化和癌症的发展。我们的详细知识 DNA修复蛋白的合成对于开发可与以下药物联合使用的药物也至关重要： 放疗或化疗，因为抑制肿瘤细胞中的DNA损伤修复将使 他们更容易接受治疗，从而更有效地治疗癌症。

Project Summary A functional machinery to repair DNA breaks is required for maintaining genome integrity and preventing tumourigenesis. In order to gain mechanistic insights into the complex DNA break repair network in mammalian cells, it is critical to identify novel factors that are required for each steps of the repair event. Equally, we need to define the roles of the known DNA break repair proteins, such as the RAD51 paralogs, as mutations in these proteins have been associated with increased cancer risks and decreased survival of cancer patients after cytotoxic therapies. Previously, We identified two of the RAD51 paralogs, RAD51C and XRCC3, as the essential components of Holliday junction resolvasome, a complex required for separate linked chromosomes during DNA break repair. This finding not only indicates a novel role of RAD51C and XRCC3 at the late stage of recombination but also in processing stalled replication forks. In addition, our studies also suggest functional interactions of the RAD51C complexes with ERCC1 and the RECQ helicases, both of which were important for processing recombination intermediates and stalled replication forks. Our goal is to define these unique functions of RAD51C complexes in recombinational repair that may explain their importance in genome maintenance and development. The Specific Aims are: (1) Identification and characterization of novel RAD51C-interacting proteins in recombinational repair. (2) Analysis of the functional relationship between RAD51C complexes and ERCC1. (3) Biochemical analysis of the functional relationship between RAD51C complexes and the RECQ proteins. Project Narrative Our research goal is to understand the complex mechanisms that repair damaged DNA, because loss of genome integrity can lead to cell transformation and cancer development. Our detailed knowledge of DNA repair proteins is also crucial for developing drugs that can be used in combination with radiotherapy or chemotherapy, since the inhibition of DNA damage repair in tumor cells would make them more susceptible to therapy, thus allowing more efficient treatment of cancer.