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研究生:簡佳怡
研究生(外文):Chia-Yi Chien
論文名稱:胸腺嘧啶核苷酸生合成之遺傳缺陷導致酵母菌細胞反應的分子生物學研究
論文名稱(外文):Molecular Studies of Cellular Response to the Genetic Defects of Thymidylate Biosynthesis in Saccharomyces cerevisiae
指導教授:蘇金源蘇金源引用關係
指導教授(外文):Jin-Yuan Su
學位類別:博士
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:英文
論文頁數:129
中文關鍵詞:出芽酵母菌胸腺嘧啶核苷酸生合成CDC8CDC21粒線體突變基因體完整性DNA損壞監控作用細胞融合
外文關鍵詞:Budding yeastThymidylate synthesisCDC8CDC21Mitochondrial mutationsGenome integrityDNA damage checkpointCell fusion
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在現代的生物科學研究當中,出芽酵母菌(Saccharomyces cerevisiae)一直是非常理想的真核生物模式之一,這主要是因為酵母菌具有巧妙的真核生物遺傳系統以及可以利用現代分子生物學技術加以操作的特性,適合用來分析基因的功能,也因此成為探討各種生物研究議題最方便的典範。就如一般的真核生物一樣,單套體的酵母菌細胞核內擁有由16條涇渭分明的染色體所組成的完整基因體,共同擔負所有的生命現象的運作。近幾年來生物學家藉著酵母菌的基因體研究,已經澄清了許多生物細胞為維護基因體完整性所進行的各種分子機制。本論文持續利用酵母菌細胞的模式試圖探討DNA前驅物之合成如何影響細胞維護基因體完整性的相互作用。
充分而適時的供應DNA前驅物;即去氧核醣核苷三磷酸(dNTPs),對於生物細胞而言是決定細胞能否準確而嚴謹地複製基因體最重要的因素之一。在細胞內的四種dNTPs中,以thymidylate的生合成途徑最為特殊,因為在兩種去氧的嘧啶類核苷酸(即thymidylate以及cytidylate)的生合成途徑中,只有thymidylate需要先合成去氧的uridylate然後再轉換成thymidylate。鑑於這種獨特性,參與在thymidylate生合成途徑的主要酵素及其作用負有決定性的地位主導DNA前驅物的提供與整個基因體是否及時複製的重任,長久以來即成為臨床醫學以及生物化學領域中令人著迷的研究主題。本論文利用參與酵母菌thymidylate生合成途徑中的兩個重要基因及其衍生的基因突變細胞,分別從細胞質及細胞核兩個角度來分析這兩個基因缺陷所形成的thymidylate合成不足,對於細胞生長以及基因體完整性所造成的影響。
真核生物的dNTPs生合成是在細胞質中進行的,大多數參與在此途徑的酵素蛋白質合成必須受到細胞分裂週期的嚴密調控以配合細胞的基因體複製期進行。酵母菌的CDC21和CDC8為參與thymidylate 生合成的兩個必需基因,其產物分別為thymidylate synthase以及thymidylate kinase兩種酵素,從過去的遺傳學研究中就已經知道這兩者是細胞核以及粒線體基因體複製所必需,而且其基因的表現也受到細胞分裂週期的調控。早期的研究曾經發現cdc21以及cdc8 的溫度敏感突變株擁有非常特殊的生長性狀,既使是培養在較低的生長允許溫度下,突變株細胞容易產生高比率的粒線體突變而導致有氧呼吸作用的缺陷,使得這類細胞生長緩慢因而形成外觀較小的菌落。可是對於此現象產生的分子機制仍不清楚。本研究利用cdc21-1突變細胞株的分析後發現在thymidylate合成不足的情況下,其細胞質中的粒線體DNA會有大量的thymidylate前驅物dUMP的堆積,因為dUMP並非正常的DNA合成原料,細胞因而啟動了由Ung1 (uracil DNA glycosylase)所催化的鹼基修補機制試圖去修補含有dUMP的粒線體基因體,在此情況下,大量的修補過程所形成的中間產物在結構上就如受到損傷的DNA因而導致粒線體的突變。
在正常情況下,單套體酵母菌具有兩種不同的交配型可以進行有性生殖的交配,交配中的細胞接觸之後,首先形成初期接合子讓雙方細胞質融合,接著再進行細胞核的融合產生擁有雙套體的接合子,之後完成雙套體細胞的發生。本研究進一步發現單套體的cdc21-1 ung1�摒蟔亄茩M株竟然失去與UNG1+ 細胞形成雙套體接合子的能力,其原因是由於cdc21-1 ung1�� 的單套體細胞核內基因體雖然已經累積有大量的dUMP,但是在缺乏Ung1的情況下細胞相安無事,可是當這個細胞與Ung1正常的細胞交配之後,Ung1在進入cdc21-1 ung1�摒蟔亄茩M核的瞬間遭遇了基因體內大量存在的dUMP因而啟動了全面性uracil鹼基修補機制,造成嚴重的DNA損傷,進而激發DNA損傷監控系統(DNA damage checkpoint)功能而阻止細胞核的融合作用。因此,本研究充分的利用酵母菌生物細胞模式分別從細胞質及細胞核的角度探討細胞針對去氧核醣核苷三磷酸thymidylate合成的遺傳缺陷所造成的影響。
The budding yeast Saccharomyces cerevisiae is considered one of the most ideal eukaryotic model systems in current biological studies. The elegance of yeast genetics and the development of modern molecular techniques in yeast allow its use for conveniently analyzing and dissecting gene functions in many biological aspects. Like in other eukaryotes, yeast possesses a defined genome, which is composed of 16 chromosomes, and is confined in a single nucleus in the haploid cell. The study of the mechanisms in maintaining the genomic integrity by using yeast as a model organism has gained a great deal of attention in recent years. This thesis is focusing on the study of how the regulation of DNA precursors synthesis would have any impact on the maintenance of genomic integrity in yeast.
An adequate and proper supply of deoxyribonucleoside triphosphates (dNTPs) is crucial for DNA replication. Among the four dNTPs, the biosynthesis of thymidylate is distinct from the other three nucleotides. Namely, in the pyrimidine biosynthesis pathway, uridylate is the first synthesized precursor which is then converted to form thymidylate. Given the unique synthesis pathway of thymidylate, the study of the enzymes involved in this pathway has been an interesting subject in either clinical or biochemical research fields. This thesis has taken advantage of two essential genes whose products are required for the biosynthesis of thymidylate in yeast and analyzed their functions to address the question of how the defect of these genes would affect the growth of yeast from both cytoplasmic and nuclear perspectives.
In eukaryotic cells, the biosynthesis of dNTPs occurs in the cytoplasm and is normally under tight control such that many enzymes involved in the synthesis of dNTPs are subject to cell cycle regulation. In the yeast, the genes encoding thymidylate synthetase (CDC21) and thymidylate kinase (CDC8) are both required for nuclear and mitochondrial DNA replication and the expression of these genes are cell cycle regulated. Early studies revealed that high frequency of respiratory-deficient petites (mitochondrial mutants) were formed in heat-sensitive cdc21 and cdc8 mutants grown at the permissive temperature. However, the molecular mechanism involved in such petite formation is largely unknown. A yeast cdc21-1 mutant was therefore used to demonstrate that the mutant cells accumulated dUMP in the mitochondrial genome as a result of the impaired thymidylate synthesis. We went on to prove that the initiation of Ung1p-mediated base excision repair in the uracil-laden mitochondrial genome in a cdc21-1 mutant is responsible for the cytoplasmic petite formation.
Sexual conjugation in the budding yeast occurs between two haploid cells of opposite mating type. Conjugation commences with cytoplasmic fusion to form a zygote followed by fusion of the two parental nuclei to produce a diploid zygote. We discovered a distinctive feature that the haploid ung1Δ cdc21-1 double mutant cells lost the ability to mate with the UNG1+ cells. The nucleus of ung1Δ cdc21-1 appeared to be completely arrested upon the conjugation with UNG1+ cell. Zygotes formed under this circumstance were, as a result, unable to complete karyogamy (nuclear fusion) and perished. We illustrated in this thesis an exceptional DNA damage checkpoint function during yeast mating. Our studies have provided, for the first time, an ideal model to characterize the DNA damage checkpoint function occurring during cell fusion.
Contents 1
中文摘要 3
Abstract 6
Introduction 9
The budding yeast as a model organism 9
Yeast life cycle 10
Cell division cycle of yeast 11
DNA damage and replication checkpoint in budding yeast 13
DNA precursor metabolism and genomic stability 17
Mitochondrion and nucleotide metabolism 23
Chapter I: 26
Abstract 27
Introduction 28
Materials and methods 30
Results and discussion 35
S-phase delay and petite formation contribute to slow growth in cdc21-1 35
Incorporation of uracil into the cdc21-1 mitochondrial genomic DNA 36
A UNG1 deletion prevents mtDNA mutations in cdc21-1 38
Mitochondrial, not nuclear, Ung1p-mediate BER triggers mtDNA mutations 40
Chapter II: 42
Abstract 43
Introduction 44
Materials and methods 48
Results and discussion 55
Deletion of UNG1 in cdc21-1 mutant causes its deficiency in diploid formation when mated with UNG1�y cell 55
The failure of ung1�� cdc21-1 double mutant to mate with wild-type cells occurs after cell fusion and before nuclear fusion 57
Functional Ung1 protein is delivered to the nucleus of ung1�� cdc21-1 cell during cell fusion and results in the termination of the mating process 59
GFP-tagged chromosome to differentiate the damaged and undamaged nuclei 62
Rad9 or Rad24 are involved in transmitting DNA damage signal in the zygote formed between ung1Δ cdc21-1 x WT 64
Chapter III: 68
Abstract 69
Introduction 70
Materials and methods 72
Results and discussion 75
Expression and analysis of the recombinant Cdc8 proteins 75
Purification of Cdc8 on Mono Q anion-exchange chromatography 76
Characterization of the TMPK and NDPK activities in Cdc8 77
Direct phosphorylation of dTDP by Cdc8 79
Tables 83
Figures 87
References 110
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