本文選題：細(xì)胞周期檢測點　切入點：拓?fù)洚悩?gòu)酶Ⅱβ結(jié)合蛋白1(TopBP1)　出處：《中國醫(yī)科大學(xué)》2006年博士論文　論文類型：學(xué)位論文

【摘要】：目的 為了保證細(xì)胞損傷后基因組的完整性，細(xì)胞通常會啟動檢測點機(jī)制以阻止細(xì)胞周期的進(jìn)展。其中兩個PIKK激酶(phosphinositide 3—kinase—like kinase，磷酸肌醇3激酶樣激酶)起著中心的作用：ATM(ataxia telangiectasia mutated，共濟(jì)失調(diào)及毛細(xì)血管擴(kuò)張癥突變蛋白)與ATR(ATM and Rad3 related，ATM與Rad3相關(guān)蛋白)。ATM被認(rèn)為負(fù)責(zé)放射損傷導(dǎo)致的檢查點阻滯的激酶，而ATR則被認(rèn)為負(fù)責(zé)復(fù)制受阻所致的基因組損傷。二者之間有互補性及簡并的功能。在ATR信號傳導(dǎo)途徑，ATR會激活并使許多下游的底物磷酸化，其中最主要的是Chkl激酶(Checkpointkinase protein 1，檢測點激酶蛋白1)。Chkl一旦被激活會進(jìn)一步作用于下游底物，其中主要為Cdc25A。而Cdc25A會進(jìn)一步調(diào)控Cdk與Cyclin復(fù)合物。迄今為止ATR—Chkl信號傳導(dǎo)途徑已是被公認(rèn)的應(yīng)答途徑。 檢查點蛋白通常被分類成如下幾類：探測蛋白，介導(dǎo)蛋白，近端信號傳導(dǎo)激酶，遠(yuǎn)端信號傳導(dǎo)激酶，效應(yīng)蛋白。其中介導(dǎo)蛋白被認(rèn)為提供場所或者在上游激酶或下游激酶進(jìn)行信號傳遞的一組蛋白。由于對損傷應(yīng)答的不同，，ATM與ATR的介導(dǎo)蛋白不同，其中Mdcl，53BP1(p53 binding protein 1，p53結(jié)合蛋白1)與BRCA1主要聯(lián)系于ATM，而Claspin(目前無對應(yīng)中文翻譯)與TopBP1(Topoisomerase Ⅱβ binding protein 1，拓?fù)洚悩?gòu)酶Ⅱβ結(jié)合蛋白1)則被認(rèn)為是ATR信號傳導(dǎo)途徑的介導(dǎo)蛋白。 TopBP1是含有8個BRCT功能域(BRCA1 C—terminus，BRCA1 C端)1522個氨基酸的蛋白。首先被認(rèn)為是DNA拓?fù)洚悩?gòu)酶Ⅱβ結(jié)合蛋白，在裂殖酵母及芽殖酵母中分別對應(yīng)為Rad4與Cut5，在細(xì)胞受到輻射后形成IRIF(Ionizing radiation induced foci，放射損傷導(dǎo)致的損傷灶)，此功能也依賴于其第5個BRCT功能域。此外，除了DNA損傷時信號的傳導(dǎo)，TopBP1還有其他的功能，是DNA復(fù)制啟動所必需的及當(dāng)復(fù)制受阻時維持復(fù)制叉的完整性，DNA的修復(fù)，可以抑制E2F1介導(dǎo)的凋亡及調(diào)節(jié)正常的S期細(xì)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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