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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張智芬 | zh_TW |
dc.contributor.advisor | Zee-Fen Chang | en |
dc.contributor.author | 趙彤 | zh_TW |
dc.contributor.author | Tung Chao | en |
dc.date.accessioned | 2023-09-28T16:14:06Z | - |
dc.date.available | 2023-11-10 | - |
dc.date.copyright | 2023-09-28 | - |
dc.date.issued | 2023 | - |
dc.date.submitted | 2023-08-06 | - |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90402 | - |
dc.description.abstract | 基因毒性可導致細胞核和粒線體內去氧核糖核酸 (DNA)的損傷並誘發細胞自噬反應,然而,粒線體DNA損傷對於維持細胞核內DNA穩定對細胞自噬的依賴性所扮演之角色尚不清楚。本研究第一部份利用特定位點的DNA損傷方法發現除非伴隨有粒線體DNA的損傷,否則細胞核內DNA損傷之修復並不需要細胞自噬的幫助。我們提供證據證明放射性照射誘導的粒線體與細胞核內DNA損傷之後若抑制細胞自噬作用會導致非凋亡性的粒線體通透性增高,促使其內的核酸內切酶G外漏至細胞質並轉移至細胞核內,進而辨認受到經由DNA活性去甲基酶TET2修飾為5-羥基化甲基化胞嘧啶(5-hmC)之DNA區域進行切割,造成核內DNA二度損傷。此外,藉由阻斷溶酶體功能就足以增加粒線體DNA瀉漏至細胞質,並伴隨粒線體核酸內切酶G瀉漏移轉至細胞核內,因此我們認為細胞自噬可以幫助清除因為粒線體DNA損傷所導致之膜通透性增高之粒線體區塊,以防止核酸內切酶G對核基因體不穩定性之影響。最後,我們還發現已知會抑制細胞自噬的乙型肝炎病毒HBx蛋白也會促使粒線體膜通透性上升導致核酸內切酶G外漏累積在細胞核中,此現象與乙型肝炎病毒誘發肝細胞癌化有關。
鑑於已知核酸內切酶G可以分解核糖核酸 (RNA),我進一步發掘核酸內切酶G能阻礙病毒RNA複製。RNA病毒感染問題是一個緊要的健康議題,了解會影響RNA病毒傳播的宿主因子對於發展抗病毒治療方法很重要。宿主細胞粒線體在先天性免疫與病毒RNA複製上扮演關鍵角色,而位於粒線體外膜上的核苷二磷酸激酶3 (NME3)已知會調控粒線體動態與氧化壓力平衡,本研究第二部份致力探討宿主細胞中的NME3對水皰性口炎病毒傳播的影響,我發現NME3缺失會抑制水皰性口炎病毒的RNA複製,宿主細胞缺乏NME3以及遭受病毒感染會使得粒線體氧化壓力提升進而導致粒線體膜通透性上升與核酸內切酶G外漏,因而降低病毒RNA複製與減少具感染性之病毒顆粒新生成,這項研究結果揭示NME3可能成為發展抗RNA病毒的治療標的,且短暫地在粒線體外表現核酸內切酶G可能得以降低病毒RNA含量而不致於造成宿主細胞凋亡。 | zh_TW |
dc.description.abstract | Genotoxic insult causes nuclear and mitochondrial DNA damages with macroautophagy/autophagy induction. The role of mitochondrial DNA (mtDNA) damage in the requirement of autophagy for nuclear DNA (nDNA) stability is unclear. In the first part of this thesis work, using site-specific DNA damage approaches, we show that specific nDNA damage alone does not require autophagy for repair unless in the presence of mtDNA damage. We provide evidence that after IR exposure-induced mtDNA and nDNA damages, autophagy suppression causes non-apoptotic mitochondrial permeability, by which mitochondrial ENDOG (endonuclease G) is released and translocated to nuclei to sustain nDNA damage in a TET (tet methylcytosine dioxygenase)-dependent manner. Furthermore, blocking lysosome function is sufficient to increase the amount of mtDNA leakage to the cytosol, accompanied by ENDOG-free mitochondrial puncta formation with concurrent ENDOG nuclear accumulation. We proposed that autophagy eliminates the mitochondria specified by mtDNA damage-driven mitochondrial permeability to prevent ENDOG-mediated genome instability. Finally, we showed that HBx, a hepatitis B viral protein capable of suppressing autophagy, also causes mitochondrial permeability-dependent ENDOG mis-localization in nuclei and is linked to hepatitis B virus (HBV)-mediated hepatocellular carcinoma development.
Considering ENDOG is capable of digesting RNAs, I further uncovered its role in suppressing viral RNA (vRNA) replication. RNA viral infection is a critical health issue. Understanding host factors influencing RNA virus propagation is important for developing antiviral therapies. Mitochondria play a crucial role in innate immunity and viral RNA replication. NME3, a member of nucleoside diphosphate kinase located on mitochondrial outer membranes, has been shown to regulate mitochondrial dynamics and ROS. The second part of this study investigated whether NME3 is a host factor that can influence the propagation of vesicular stomatitis virus (VSV). I demonstrated that NME3 depletion suppressed VSV RNA replication. Our mechanistic investigation revealed that NME3 deficiency and viral infection elevated mitochondrial oxidative stress to promote mitochondrial endonuclease G (ENDOG) leakage. As a result, ENDOG-mediated elimination of viral RNAs reduced infectious virion production. Our findings suggested that NME3 might be a potential target for developing anti-RNA virus agent, and transient overexpression of ENDOG outside mitochondria may reduce vRNAs without leading to apoptotic cell death. | en |
dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-28T16:14:06Z No. of bitstreams: 0 | en |
dc.description.provenance | Made available in DSpace on 2023-09-28T16:14:06Z (GMT). No. of bitstreams: 0 | en |
dc.description.tableofcontents | Table of contents
博士學位論文口試委員會審定書 i 謝誌 ii 中文摘要 iii Abstract v Table of contents vii Chapter I-Overview and Rationale 1 Preface 2 Introduction 2 Mitochondrial DNA damages and quality control 2 The molecular structures, functions, and regulation of the mitochondrial permeability transition pore 4 The functional roles of endonuclease G 7 Rationale 9 Chapter II-Autophagy restricts mitochondrial DNA damage-induced release of endonuclease G to regulate genome stability 10 Introduction 11 Materials and Methods 13 Results 22 Discussion 34 Figures 39 Chapter III-Depletion of NME3 suppresses viral RNA replication via mitochondrial leakage of endonuclease G 75 Introduction 76 Materials and Methods 77 Results 89 Discussion 102 Figures 107 References 136 Appendix 154 | - |
dc.language.iso | en | - |
dc.title | 探討粒線體於調控基因體穩定性與RNA病毒在宿主細胞內繁殖之角色 | zh_TW |
dc.title | Investigation into the mitochondria regulation in genome stability and RNA virus propagation | en |
dc.type | Thesis | - |
dc.date.schoolyear | 111-2 | - |
dc.description.degree | 博士 | - |
dc.contributor.oralexamcommittee | 陳培哲;張淑媛;徐立中;劉雅雯 | zh_TW |
dc.contributor.oralexamcommittee | Pei-Jer Chen;Sui-Yuan Chang;Li-Chung Hsu;Ya-Wen Liu | en |
dc.subject.keyword | 細胞自噬,核酸內切酶G,基因體不穩定性,粒線體通透性,粒線體去氧核糖核酸,核苷二磷酸激酶3,病毒核糖核酸複製,水皰性口炎病毒, | zh_TW |
dc.subject.keyword | autophagy,endonuclease G,genome instability,mitochondrial permeability,mitochondrial DNA,nucleoside diphosphate kinase,viral RNA replication,vesicular stomatitis virus, | en |
dc.relation.page | 154 | - |
dc.identifier.doi | 10.6342/NTU202303194 | - |
dc.rights.note | 同意授權(限校園內公開) | - |
dc.date.accepted | 2023-08-07 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 分子醫學研究所 | - |
顯示於系所單位: | 分子醫學研究所 |
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