臺灣博碩士論文加值系統

DNA損害檢驗點(DNA damage checkpoint)最早是由酵母菌的研究發現。此機制在真核生物中維持基因的穩定，透過控制細胞週期與活化DNA 修復基因，保護著複製前、中、後基因的完整性。Ataxia telangiectasia and Rad3 related protein (ATR) 為哺乳類的複製週期檢查點 (replication checkpoint)，其訊息傳遞路徑位於上游的主要磷酸&;#37238;。研究顯示缺少ATR的老鼠，在胚胎生長時期，細胞快速複製所產生的複製壓力，使老鼠產生早衰的現象。為更進一步了解checkpoint在細胞老化中扮演的角色，我們使用ATR在酵母菌中的同源基因MEC1磷酸&;#37238;，與其下游基因RAD53磷酸&;#37238;功能突變的酵母菌株mec1-100和rad53-11，分析其生殖壽命 (replicative life span)，發現突變株的壽命確實縮短。因此藉由能夠調節生殖壽命的基因和相關路徑，包括延長壽命最有效果的熱量限制，和在酵母菌的老化研究中控制生殖壽命的重要因素ribosomal-DNA (rDNA)、配位基因(mating loci) 與端粒 (telomeres) 區域穩定性，來分析mec1-100和rad53-11與這些路徑的交互的影響。結果顯示熱量限制無法提升突變株的壽命，推測需有Mec1及Rad53的磷酸化的功能下，才能使熱量限制發揮延長壽命的效果。我們更進一步剔除維持老化相關區域穩定的Sir2蛋白後，其生殖壽命更加縮短，並且也發現失去MEC1和RAD53的功能確實造成rDNA, mating loci, telomere不穩定的現象。因此結果顯示，細胞複製檢查點的功能與Sir2共同維持片段穩定，但與Sir2路徑不同。推測其破壞基因穩定性的機制可能需要往由於缺陷而累積的複製壓力做進一步的探討，因此我們參考了近年老化研究在組蛋白 (histone) 修飾或是核小體 (nucleosome)組裝對於壽命的影響，推測checkpoint突變株無法處理複製壓力，產生核小體組裝問題，進而造成染色體不穩定而老化。我們分析剔除會使telomeres區域包裝更完整的乙醯基轉移基因SAS2，但mec1-100和rad53-11中進一步剔除SAS2，結果發現大幅縮
短了mec-100的壽命。推測可能過度緊密而產生複製壓力，亦或抑制了修補蛋白的進入。我們也剔除伴蛋白(histone chaperone) Asf1和控制組蛋白生成的Hir3，來模擬了老化失去組蛋白的情形和增加基因組蛋白的包裝而延長壽命。結果顯示在asf1突變株中，剔除了Mec1的功能其壽命不變，而在hir3Δ也能延長壽命，而在rad53-11背景中則都是縮短壽命。推論checkpoint功能缺失所造成老化與組蛋白失去是相關的，但因mec1-100仍擁有G2/M的checkpoint 功能，而在rad53-11細胞中是缺失的，才會有如此差異。此研究顯示酵母菌細胞擁有正常的checkpoint功能，才能使熱量限制發揮延長壽命的效果。另外checkpoint 的功能缺失會造成老化現象，其路徑與sir2Δ不同，可能機制為細胞無法處理複製壓力，造成複製時不適當histone組裝的區域變多，進而對基因組產生傷害，因此與老化相關的DNA區域都會受到影響。

Replication checkpoints serve as control mechanisms that ensure the fidelity of the replicating genome in eukaryotes. It was previously reported that a mouse model of checkpoint (ATR) deficiency exhibited replicative stress during embryogenesis, which resulted in premature aging. To further understand the role of the replication checkpoint in cellular aging, we took advantage of the ATR homologous gene MEC1 and its hypostatic gene RAD53 in yeast. We determined the replicative lifespans (RLS) of the hypomorphic mec1-100 and rad53-11 mutants; the life span of these mutants was decreased significantly as compared to the wild type strain. Therefore, we examined the genes and pathways that modulate RLS to establish the relevance of checkpoint function in cellular aging. We found that calorie restriction (CR) required the checkpoint kinase function of Mec1 and Rad53 to extend life span. We further demonstrated that checkpoint function is required to protect the stability of the rDNA array, mating loci and telomeres but this is independent of the protection by sirtuins Sir2. Moreover, while a defect in chromatin assembly (the asf1Δ mutation) did not further decrease the life span of mec1-100, it did decrease that of rad53-11. Furthermore, an increased histone supply (hir3Δ) extended the lifespan of mec1-100 cells, but not those of rad53-11. Deletion of histone acetyltransferase SAS2 results in tighter packaging of telomere and life span extension; surprisingly, mec1-100 and rad53-11 mitigate the life span extension effect of sas2Δ with the decrease being greatest in mec1-100. Collectively, our results suggest that the kinase function of Mec1 and Rad53 mediates the effect of calorie restriction on replicative life span extension. The genetic analyses reveal that the checkpoint pathway may contribute to preserving chromatin integrity in both heterochromatin (rDNA and telomere) and euchromatin (active chromatin). We propose that loss of function of the checkpoint kinase may cause aging due to failure to respond replicative stress, which increases of sporadic damage to the genome when chromatin is improperly assembled.

謝誌 i
國立臺灣大學碩士學位論文 ii
口試委員會審定書 ii
摘要 iii
ABSTRACT v
CONTENTS v
LIST OF FIGURES ix
LIST OF TABLE x
CHAPTER 1 INTRODUCTION 1
CHAPTER 2 LITERATURE REVIEW 2
2.1 Saccharomyces cerevisiae 2
2.1.1 Budding yeast as a model organism 2
2.1.3 Replicative aging 6
2.2 Cell cycle checkpoint 8
2.2.1 Importance of the cell cycle checkpoint 8
2.2.2 Replication checkpoint pathway 10
2.2.3 Checkpoint kinase: Mec1 versus Rad53 12
2.3 Genes and pathways modulating replicative life span 16
2.3.1 Well-studied mechanism of replicative aging in yeast 16
2.3.2 Calorie restriction 18
2.3.3 The effect of Silence information regulator on replicative life span 20
2.3.4 Chromatin remodeling and aging 24
2.4. Checkpoint and aging 29
CHAPTER 3 MATERIALS AND METHODS 32
3.1 Experimental design 32
3.2 Materials 32
3.2.1 Yeast strains 32
3.2.2 Media 34
3.2.3 Autoclave conditions 34
3.3 Methods 35
3.3.1 Yeast culture 35
3.3.2 Spotting assay 35
3.3.3 Pheromone Halo assay 36
3.3.4 Unequal sister chromatid exchange assays 37
3.3.5 Replicative lifespan measurement 38
3.3.6 Cell cycle progression analysis 39
CHAPTER 4 RESULTS 41
4.1 Short life span caused by mutation of Mec1 and Rad53 kinase function. 41
4.2 The checkpoint is required for the life extension effect of calorie restriction. 45
4.3 The checkpoint and rDNA stability 47
4.3.1 The checkpoint regulates aging through a Sir2 independent pathway . 47
4.3.2 The checkpoint regulates aging through mutiple pathways involving FOB1 deletion in the rDNA region. 50
4.3.3 Mutation of the checkpoint increases rDNA recombination. 53
4.4 The silencing of mating loci is affected in a checkpoint kinase mutant. 55
4.5 Regulating lifespan through histone remodeling pathways 59
4.5.1 Histone assembly dysfunction may underlie accelerated aging in checkpoint mutant 59
4.5.2 The life extension effect of SAS2 deletion require DNA damage checkpoint 61
4.5.3 The effect of elevating histone supply, or disrupting histone assembly factor on mec1-100 and rad53-11 64
CHAPTER 5 DISCUSSION 68
5.1 Observation of stochastic cell death particularly of mec1-100 cells 68
5.2 Checkpoint proteins Mec1 and Rad53 might may play roles inmediate the effects of calorie restriction 74
5.3 The effect of checkpoint mutants on age related DNA region 76
5.4 The effect of histone remodeling on checkpoint mutants 69
CHAPTER 6 CONCLUSIONS 78
CHAPTER 7 REFERENCES 80

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