2013-01-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/680903摘要：細胞的遺傳物質去氧核糖核酸 (DNA) 持續性的遭受不同形式的損害，在這之中，雙股 DNA 的斷裂是最嚴重的染色體損傷。如果細胞未適當的修復斷裂的 DNA，會導致染色體的異常及遺傳物質的不穩定性。同源重組 (Homologous Recombination) 不僅是細胞主要修復 DNA 斷裂的機轉；而且不適當同源重組的調控，也會促成染色體的異變甚至癌症的發生。所以細胞具有嚴密的機制來調控同源重組的進行。同源重組反應的起始是由 Rad51 重組酵素 (Recombinase) 所催化。Rad51 蛋白會結合單股 DNA，形成核蛋白聚合物 (nucleoprotein filament) 並將單股 DNA 與同源的雙股 DNA 進行交換，以完成同源重組反應。即使我們對同源重組反應的瞭解有所進展，我們仍缺乏闡明 Rad51 重組酵素和其交互作用的蛋白彼此調控的分子機轉。在最近老鼠與人類細胞株的遺傳學和細胞學研究指出 Swi5-Sfr1 和 SWS1-SWSAP1 蛋白複合體參與同源重組的 DNA 修復並促進 Rad51 的同源重組反應；但是 Swi5-Sfr1 和 SWS1-SWSAP1 蛋白複合體對於 Rad51 活性的調控機制至今尚未明瞭。在這份研究申請書，我們將探討及闡釋 Swi5-Sfr1 和 SWS1-SWSAP1 蛋白複合體參與 Rad51 重組反應的分子作用機制。此研究的成果將有助於提供預防及藥物研發的策略與基礎來治療因同源重組反應失控所導致的人類疾病，例如癌症。<br> Abstract: Cells continually sustain various types of DNA damage. Among them double strand breaks (DSBs) are the most lethal chromosomal lesions, which if remain unrepaired, can lead to genome instability. Homologous recombination (HR) mediated repair not only represents a major error free repair pathway to eliminate deleterious DSBs, but inappropriate recombination also leads to chromosomal abnormalities and cancer formation. To maintain genome stability cells have evolved unique mechanisms to regulate homologous recombination. Recombination is initiated by Rad51 recombinase, an enzyme forming a nucleoprotein filament onto single strand DNA (ssDNA) and exchanging the ssDNA with the homologous double strand DNA (dsDNA) to complete recombination. Even though we have a great progress on understanding the recombination pathway, it remains mysterious at the mechanistic level how recombinase and their associated partners fulfill their biological task. Recently genetic and cytological studies from mouse and human cell lines have identified new Swi5-Sfr1 and SWS1-SWSAP1 protein complexes that possess a significant role in recombinational repair and facilitate Rad51-mediated recombination. However the detailed mechanistic study on the functional interaction of mammalian Swi5-Sfr1, SWS1-SWSAP1 and Rad51 remains largely unknown. The study proposed herein will address and shed light on the action mechanism between recombinase and their interacting components during recombinational processes. The molecular insights garnered from this study could potentially provide the basis for devising the strategies for prevention and treatment of various cancers that arise because of HR deficiency or inappropriate regulation.同源重組去氧核糖核酸修復Rad51重組酵素Swi5-Sfr1蛋白複合體SWS1-SWSAP1蛋白複合體Homologous recombinationDNA repairRad51 recombinaseSwi5-Sfr1SWS1-SWSAP1