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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 鄧述諄 | |
| dc.contributor.author | Chia-Wei Yang | en |
| dc.contributor.author | 楊家維 | zh_TW |
| dc.date.accessioned | 2021-06-17T02:01:48Z | - |
| dc.date.available | 2017-09-12 | |
| dc.date.copyright | 2017-09-12 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-07-18 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67978 | - |
| dc.description.abstract | 端粒的穩定由端粒酶與末端保護機制所調控。過短的端粒會活化DNA損傷感應激酶ATM/ATR並作用於端粒酶的聚集。然而，端粒的縮短是否也調控著末端保護機制仍然不甚清楚。在此，我揭示了一種反饋端保護的機制，此藉由酵母ATM/ATR控制著末端保護。Rap1的第731號絲氨酸處可被Tel1和Mec1激酶所磷酸化，而DNA損傷和端粒的縮短會促進該位點的磷酸化。Rap1磷酸化的缺失會降低Rap1與其相互作用的配偶體Rif1之間的相互作用，進而削弱了末端保護的強度。Rap1-Rif1結合的減少會損害端粒長度的調控並增加端粒與端粒間的重組機會。然而，受損的Rap1磷酸化既不影響端粒與端粒間的融合也不影響端粒沉默。這些結果顯示ATM/ATR的DNA損傷檢查點信號能藉由加強於短端粒上的Rap1-Rif1相互作用來控制端粒保護，檢查點激酶調節端粒酶的聚集與末端保護的途徑以維持端粒的穩定。 | zh_TW |
| dc.description.abstract | Telomere homeostasis is regulated by both telomerase and end protection mechanisms. Short telomere can activate DNA damage sensing kinases ATM/ATR for telomerase recruitment. However, it is still not clear whether telomere shortening also regulates end protection. Here I reveal a feedback end protection mechanism which regulated by yeast ATM/ATR under telomere stress. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this phosphorylation is strengthened by DNA damage and telomere shortening. Loss of Rap1 phosphorylation decreases the interaction between Rap1 and its interacting partner Rif1, which further weakens the strength of end protection. Reduction of Rap1-Rif1 association impairs telomere length regulation and increases the change of telomere-telomere recombination. However, impaired Rap1 phosphorylation neither influences the telomere-telomere fusion nor the telomeric silencing. These results indicate that ATM/ATR DNA damage checkpoint signal controls the telomere protection by strengthening the Rap1-Rif1 interaction at short telomere, and the checkpoint kinase regulates both telomerase recruitment and end capping pathways to maintain telomere homeostasis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T02:01:48Z (GMT). No. of bitstreams: 1 ntu-106-F97445105-1.pdf: 3972386 bytes, checksum: 0969d9db68efb911a8b8d3f37f3f3426 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | CONTENTS i
口試委員會審定書 vii 致謝 ix 中文摘要 xi ABSTRACT xiii INTRODUCTION 1 Telomere and its shortening 1 Yeast telomere and telomeric binding protein Rap1 3 DNA damage response and telomere capping 5 Capping proteins in budding yeast 6 Tel1/Mec1 kinase and short telomere 8 RESULTS 11 Phosphorylation of Rap1 serine 731 regulates telomere length, but not silencing effect. 11 Telomere shortening stimulates Tel1 and Mec1 to directly phosphorylate Rap1 S731. 13 Phosphorylation of Rap1 S731 promotes the interaction with Rif1, but not Rif2. 16 Rap1 S731 phosphorylation facilitates the Rif1 loading onto telomeres. 19 Rap1 S731 phosphorylation does not modulate the Sir3 occupancy on telomeres. 20 Rap1 S731 phosphorylation inhibits type II telomere-telomere recombination. 21 Rap1 phosphorylation-mediated telomere length regulation depends on Cdc13 phosphorylation-mediated telomerase recruitment. 22 DISCUSSION 25 MATERIALS & METHODS 31 Strains and plasmids 31 Southern blot analysis of telomere length 33 Telomeric and mating-type locus silencing assays 34 Immunoprecipitation, generation of phospho-specific antibodies and λ phosphatase assays 35 Dot blot assay 36 Cell cycle analysis 36 Co-immunoprecipitation (Co-IP) 36 Pull-down assay 37 Chromatin immunoprecipitation (ChIP) assay 38 In vitro kinase assay 39 Electrophoretic Mobility Shift Assay (EMSA) 41 Yeast two-hybrid assay 41 Amplification of the telomere-telomere fusions by PCR 42 Statistical Analysis 43 FIGURES AND FIGURE LEGENDS 45 Figure 1. Phosphorylation of Rap1 serine 731 modulates telomere length regulation. 45 Figure 2. Telomere analysis of rap1 mutants in YPH499 and W303-1A backgrounds. 47 Figure 3. Deficiency of Rap1 S731 phosphorylation does not attenuate telomere position effect and mating type locus silencing. 48 Figure 4. Characterization of the phospho-specific antibodies against Rap1 S731. 49 Figure 5. DNA damage and telomere shortening increases Rap1-S731 phosphorylation. 50 Figure 6. Telomere analysis and Rap1-S731 phosphorylation of pif1-m2 and cdc13-S314A mutants containing Myc13-tagged Rap1. 52 Figure 7. Tel1/Mec1-mediated Rap1 phosphorylation on S731 is associated with telomere length variation. 53 Figure 8. Phosphorylation of Rap1 S731 is cell cycle-independent. 55 Figure 9. Telomere analysis of WT, rap1-S731A and rap1-S731D mutations in the rif1 background. 56 Figure 10. Complementation of Rif1 restored the telomeres shortening phenotype of rap1-S731D, while the telomeres remained elongated at the initial back-crossing stage. 57 Figure 11. Telomere analysis of WT, rap1-S731A and rap1-S731D mutations in the rif2 background. 59 Figure 12. Telomere analysis of WT, rap1-S731A and rap1-S731D mutations in the rif1 rif2 background. 60 Figure 13. Telomere analysis of WT, rap1-S731A, and rap1-S731D in the yku80 background. 61 Figure 14. The total Rap1 amounts are comparable between WT, rap1-S731A and rap1-S731D cells in the rif1, rif2 and rif1 rif2 backgrounds. 62 Figure 15. Rap1 S731A mutation reduces its interaction with Rif1, but not Rif2. 63 Figure 16. Rif1, but not Rif2, occupancy at telomeres is reduced in rap1-S731A cells. 65 Figure 17. EMSA assay of Rap1 fusion proteins showed no noticeable change of the Rap1 binding affinity to telomeric DNA sequence. 67 Figure 18. Absence of phosphorylation does not change the Rap1-Sir3 interaction. 69 Figure 19. Telomere lengthening phenotype of rap1-S731A was abrogated in cdc13-S249/S255A cells. 71 Figure 20. ATM/ATR kinases activate different downstream signaling pathways to circumvent progressive telomere shortening puzzle. 73 Figure 21. Tel1 orchestrates the telomere capping and telomerase recruitment pathways in telomere-shortened cells. 74 Figure 22. Rap1-S731 phosphorylation might increase Rif1 abundance and its recruitment onto telomeres. 75 Figure 23. In silico specificity screens of ChIP primers. 76 Figure 24. RT-qPCR assay performance in accordance with MIQE guidelines. 79 TABLES 81 Table 1. Putative phosphorylation sites of Rap1 81 Table 2. Distribution of survivor types. 82 Table 3. Strains Used in This Study. 83 Table 4. Constructs Used in This Study. 88 Table 5. Primers Used in This Study. 89 Table 6. MIQE Guidelines Checklist. 93 Table 7. Reaction Conditions for qPCR. 103 REFERENCES 105 APPENDIXES 115 Appendix I Figures Contributed by Other Authors 115 Figure S1. Effects of Rap1-S731 mutations in Yeast-Two hybrid assay. 116 Figure S2. Rap1 S731 phosphorylation does not modulate telomere-telomere fusions. 117 | |
| dc.language.iso | en | |
| dc.subject | 端粒 | zh_TW |
| dc.subject | 保護 | zh_TW |
| dc.subject | 端粒? | zh_TW |
| dc.subject | Rap1 | zh_TW |
| dc.subject | ATM/ATR | zh_TW |
| dc.subject | Telomere | en |
| dc.subject | telomerase | en |
| dc.subject | Rap1 | en |
| dc.subject | ATM/ATR | en |
| dc.subject | capping | en |
| dc.title | 端粒縮短誘發回饋迴圈以增進末端保護 | zh_TW |
| dc.title | Telomere shortening Triggers a Feedback Loop to
Enhance End Protection | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 林敬哲,李財坤,吳青錫,劉雅雯 | |
| dc.subject.keyword | 端粒,保護,端粒?,Rap1,ATM/ATR, | zh_TW |
| dc.subject.keyword | Telomere,capping,telomerase,Rap1,ATM/ATR, | en |
| dc.relation.page | 118 | |
| dc.identifier.doi | 10.6342/NTU201701682 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-07-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| Appears in Collections: | 微生物學科所 | |
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