TopBP1蛋白在细胞DNA损伤中的作用机制

发布时间：2018-03-13 19:04

  本文选题：细胞周期检测点　切入点：拓扑异构酶Ⅱβ结合蛋白1(TopBP1)　出处：《中国医科大学》2006年博士论文　论文类型：学位论文

【摘要】：目的 为了保证细胞损伤后基因组的完整性，细胞通常会启动检测点机制以阻止细胞周期的进展。其中两个PIKK激酶(phosphinositide 3—kinase—like kinase，磷酸肌醇3激酶样激酶)起着中心的作用：ATM(ataxia telangiectasia mutated，共济失调及毛细血管扩张症突变蛋白)与ATR(ATM and Rad3 related，ATM与Rad3相关蛋白)。ATM被认为负责放射损伤导致的检查点阻滞的激酶，而ATR则被认为负责复制受阻所致的基因组损伤。二者之间有互补性及简并的功能。在ATR信号传导途径，ATR会激活并使许多下游的底物磷酸化，其中最主要的是Chkl激酶(Checkpointkinase protein 1，检测点激酶蛋白1)。Chkl一旦被激活会进一步作用于下游底物，其中主要为Cdc25A。而Cdc25A会进一步调控Cdk与Cyclin复合物。迄今为止ATR—Chkl信号传导途径已是被公认的应答途径。 检查点蛋白通常被分类成如下几类：探测蛋白，介导蛋白，近端信号传导激酶，远端信号传导激酶，效应蛋白。其中介导蛋白被认为提供场所或者在上游激酶或下游激酶进行信号传递的一组蛋白。由于对损伤应答的不同，，ATM与ATR的介导蛋白不同，其中Mdcl，53BP1(p53 binding protein 1，p53结合蛋白1)与BRCA1主要联系于ATM，而Claspin(目前无对应中文翻译)与TopBP1(Topoisomerase Ⅱβ binding protein 1，拓扑异构酶Ⅱβ结合蛋白1)则被认为是ATR信号传导途径的介导蛋白。 TopBP1是含有8个BRCT功能域(BRCA1 C—terminus，BRCA1 C端)1522个氨基酸的蛋白。首先被认为是DNA拓扑异构酶Ⅱβ结合蛋白，在裂殖酵母及芽殖酵母中分别对应为Rad4与Cut5，在细胞受到辐射后形成IRIF(Ionizing radiation induced foci，放射损伤导致的损伤灶)，此功能也依赖于其第5个BRCT功能域。此外，除了DNA损伤时信号的传导，TopBP1还有其他的功能，是DNA复制启动所必需的及当复制受阻时维持复制叉的完整性，DNA的修复，可以抑制E2F1介导的凋亡及调节正常的S期细胞周期等等。
[Abstract]:Purpose. To ensure the integrity of the damaged genome, Cells usually activate the detection point mechanism to block cell cycle progression. Two PIKK kinases, phosphinositide 3-kinase-like kinases, phosphoinositide 3-kinase-like kinases (phosphoinositol 3-kinase-like kinases) play a central role, ataxia telangiectasia mutated, ataxia ataxia mutated, ataxia, and telangiectasia mutated proteins. ATR(ATM and Rad3 related ATM- and Rad3 related proteins, ATMs, are thought to be responsible for radiation-induced checkpoint arrest kinases. ATR, on the other hand, is thought to be responsible for genome damage caused by blocked replication. There are complementary and degenerate functions between the two. In the ATR signaling pathway, ATR activates and phosphorylates many downstream substrates. The most important of these is the Chkl kinase Checkpoint kinase protein 1. Once the detection point kinase protein 1, Chkl, is activated, it further acts on the downstream substrate. Cdc25A. Cdc25A further regulates the complex of Cdk and Cyclin. Up to now, ATR-Chkl signaling pathway has been recognized as a response pathway. Checkpoint proteins are generally classified into the following categories: detection proteins, mediating proteins, proximal signal transduction kinases, distal signal transduction kinases, Effector protein. A group of proteins in which mediating proteins are thought to provide a site or signal transduction in upstream or downstream kinases. Among them, Mdcl-53BP1-p53 binding protein 1-p53 binding protein 1 is mainly associated with BRCA1, while Claspin (without corresponding Chinese translation) and TopBP1(Topoisomerase 鈪

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