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研究生:王慈涵
研究生(外文):Tzu-Han Wang
論文名稱:探討polyQ蛋白產生聚集時分子間的交互作用以及Bem2p對CAA/CAG重複序列穩定性的影響
論文名稱(外文):The study of inter-molecular interaction between polyQ strands that promote polyQ-containing proteins co-aggregation and the role of Bem2p plays in the DNA stability of repetitive sequence that encodes polyQ
指導教授:鄭子豪
指導教授(外文):Tzu-Hao Cheng
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:72
中文關鍵詞:蛋白質聚集亨丁頓舞蹈症三核苷酸重複序列
外文關鍵詞:aggregationHuntington's diseaserepetitive sequenceBEM2polyQ
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1.亨丁頓舞蹈症是一種神經退化性疾病,由huntingtin (htt) exon 1上過多的CAG重複序列所造成,並且經由體染色體顯性遺傳。當CAG重複序列達到36次以上時,就會產生疾病。帶有過長CAG重複序列的 Htt基因產物容易產生聚集的現象,且在病人腦部中產生Htt蛋白聚集體,因此成為此疾病一項重要的特徵。過去的研究中指出,除了異常蛋白質會有聚集現象外,在聚集的過程中也會將帶有正常polyQ的蛋白質聚集在聚集體中,產生共同聚集的現象。爲了更近一步了解這些不同分子之間如何相互作用產生聚集,並尋找一種具有抑制聚集發生的突變基因,我們設計了一個新穎的細胞篩選系統來觀察蛋白質共同聚集的現象;並將polyQ序列做隨意的胺基酸突變建構成一library,以此進行篩選。經過三次的篩選,我們發現當細胞同時表達一經由突變造成縮短的polyQ蛋白質時,會使異常蛋白質的聚集產生些微下降的情形,然而這樣的結果可能是異常蛋白質表現量降低所致。
2.在酵母菌中,BEM2基因調控細胞分裂時的極性。這個蛋白質在C端帶有一個GAP domain,因此可以用來調控含有GTPases活性的蛋白質。在酵母菌的研究中,含有GTPase活性的蛋白質,像是CDC42, RHO1, RHO2, RHO3, 和 RHO4能夠藉由調控肌動蛋白 (actin)以及細胞型態來影響出芽生殖。我們利用Snyder’s knock out library進行實驗,意外發現當細胞失去BEM2基因的功能時,會造成CAA/CAG重複序列產生不穩定的現象並且經由DNA重組而縮短,因此BEM2能調控重複序列的穩定性。另ㄧ方面,我們證實bem2△所造成DNA不穩定的原因來自於細胞失去Bem2p所調控的morphogenesis checkpoint功能;再加上在swe1△造成morphogenesis checkpoint缺失的細胞中同樣也可觀察到DNA縮短比率上升,因此在我們的研究顯示,酵母菌中重複序列穩定性的調控與morphogenesis checkpoint功能之間是具有關聯性的。
1.Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder and is caused by the expansion of CAG repeats, encoding polyglutamines (polyQ), within exon 1 of the huntingtin (htt) gene. The length of polyQ track is a main determinant for the onset of HD and the disease occurs only when the critical length of ~36 glutamines is exceeded. A peculiar feature of mutant htt proteins with abnormal length of polyQ is that they spontaneously self-assemble into aggregates, a pathological hallmark of this disorder found in the brain of affected individuals. Several studies have demonstrated that proteins with normal length of polyQ track can also interact with and recruit into these aggregates, which are initiated by polyQ-expanded proteins. In order to further investigate this inter-molecular interaction between heterogeneous polyQ strands and to find a potential dominant negative mutant that can interfere with the formation of polyQ aggregates in cells, we have established a phenotypic assay system that can reveal the presence of co-aggregation and costructed a library of amino acid substitution within the polyQ track for examining their effect on polyQ aggregation. After three rounds of screening, we find that co-expression of truncated polyQ peptides can partially reduce the aggregation levels of 97Q protein. However, this effect may result from decreased 97Q expression.
2.The BEM2 gene is required for normal polarized cell growth in the budding yeast Saccharomyces cerevisiae. In the carboxyl-terminus, Bem2p contains a GAP domain, which is commoly found in GTPase activating proteins (GAPs) that regulate rho-GTPase activity. In yeast, genes encoding GTPases (CDC42, RHO1, RHO2, RHO3, and RHO4) have been proposed to regulate cellular morphogenesis such as actin cytoskeleton and bud emergence. Using the Snyder’s knock out library, we find that bem2△ mutations confer DNA repetitive sequence instability and enhance contraction of CAA/CAG repeats through homologous recombination, suggesting Bem2p has a role in regulating DNA stability. We also demonstrate the DNA instability is attributed to the defective function of Bem2p in morphogenesis checkpoint. Furthermore, swe1, a△ morphogenesis checkpoint deficient cell, shows an elevated DNA contraction rate. Thus, our study reveals a novel link between morphogenesis checkpoint and repetitive sequence stability in yeast cells.
目錄......................................................i
中文摘要 ..............................................1
Abstract ..............................................2
緒論 ..................................................3
一、 亨丁頓舞蹈症與Htt蛋白質上異常延伸的polyQ...........3
二、 異常Htt蛋白質的聚集以及神經細胞的死亡..............4
三、 polyQ蛋白質在細胞中形成共同聚集(co-aggregation)的現象 ....................................................5
四、 利用在polyQ序列上隨機的突變來進行蛋白質聚集的篩選 ....................................................6
材料與方法................................................7
材料 ..................................................7
方法 .................................................15
結果 .................................................21
一、 在酵母菌中建構ㄧ用來探討polyQ蛋白interaction之篩選系 統 ...................................................21
二、 pYES2-25Q-GFP library篩選.........................23
討論 .................................................25
中文摘要 .............................................29
Abstract .............................................30
緒論 .................................................31
一、 BEM2在細胞中的功能................................31
二、 polyglutamine diseases與三核苷酸重複序列的穩定....32
三、 細胞週期中Morphogenesis checkpoint的調控..........33
結果 .................................................34
一、 探討BEM2對CAA/CAG序列穩定性的影響................34
二、 探討Morphogenesis checkpoint與重複序列穩定性之關連 ...................................................36
三、 BEM2藉由homologous recombination影響CAA/CAG的穩定性 ...................................................36
四、 探討RAD系列基因在BEM2調控重複序列穩定性之影響.....37
討論 .................................................40
參考文獻 .............................................44
圖表 .................................................53
Figure 1. Co-expression of protein with expanded polyQ repeats changes the colony color phenotype of cells expressing 25Q-ADE2......................................53
Figure 2. Co-expression of protein with expanded polyQ repeats changes the colony color phenotype of cells expressing 25Q-ADE2-S-tag................................54
Figure 3. Protein with 25Q repeats forms co-aggregation with expanded polyQ protein ..........................55
Figure 4. Protein with 25Q repeats forms aggregated foci only in the presence of expanded polyQ protein within cells ................................................56
Figure 5. Co-expression of protein with expanded polyQ repeats changes the colony color phenotype of cells expressing 25Q-ADE2......................................57
Figure 6. Flow chart of the polyQ mutation library screening ............................................58
Figure 7. Reconfirmation of colony colors of candidates selected from 25Q mutation library screening.............59
Figure 8. Mutation profile of pYES2-25Q-GFP..............60
Figure 9. The clones that reappeared pink/white color phenotype after re-transformation........................61
Figure 10. Co-expression of truncated polyQ peptides can partially reduce the aggregation levels of 97Q protein...62
Figure 11. bem2 GAP△ white cells abrogate polyQ aggregation, resulting from the decrease of polyQ repeats in reporter protein......................................63
Figure 12. The length of polyQ repeats in bem2 GAP△ white cells....................................................64
Figure 13. Expression of exogenous BEM2 restores CAA/CAG stability ............................................65
Figure 14. Bem2p GAP activity and actin localization.....66
Figure 15. The GAP activity of Bem2p is dispensable for its checkpoint function......................................67
Figure 16. Bem2p dose not require its GAP activity to maintain the the stability of CAA/CAG sequence ..........68
Figure 17. The contraction of CAA/CAG repetitive sequence is increased when cells are defective in morphogenesis checkpoint...............................................69
Figure 18. The effect of Rad27p, Rad51p,Rad52p on the stability of CAA/CAG repetitive sequence.................70
Table 1. Nutrient concentrations for dropout powers.....71
Appendix 1. Color base system for detecting polyQ-mediated protein aggregation......................................72
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