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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳小梨(Show-Li Chen) | |
dc.contributor.author | Li-Po Wang | en |
dc.contributor.author | 汪立博 | zh_TW |
dc.date.accessioned | 2021-06-15T13:34:22Z | - |
dc.date.available | 2021-02-23 | |
dc.date.copyright | 2021-02-23 | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021-02-08 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51442 | - |
dc.description.abstract | BCAS2在調控pre-mRNA剪接、有絲分裂時的紡錘絲形成,以及雄激素受體轉錄時都扮演關鍵的角色。也有之前的研究提及BCAS2參與DNA的修復作用,但詳細的機制還不清楚。我們實驗室提供證據顯示在人類前列腺癌細胞株中,BCAS2的表現可以保護細胞抵抗游離輻射 (IR) 造成的雙股DNA斷裂損害。我們也用果蠅翅成蟲盤組織做模式,證明BCAS2大量表現能夠舒緩輻射線造成的細胞凋亡。為了進一步探討BCAS2對雙股DNA斷裂修復的機制,實驗結果指出,BCAS2對於兩種主要的修復途徑,非同源末端连接 (non-homologous end joint, NHEJ) 以及同源重组修復 (Homologous Recombination, HR) 分別都有促進的作用。我們也證明BCAS2能夠用其N端片段與NBS1的N段及C端直接結合,NBS1是MRN complex (MRE11/RAD50/NBS1) 的一員,在DNA修復及細胞生理週期調控都是不可或缺的。因此我們提出,BCAS2經由結合並促進NBS1聚集到DNA斷裂點,增進雙股DNA修復的效率。最後我們發現在前列腺癌患者樣本上,BCAS2與另一個腫瘤生物標記β-catenin,都在惡性腫瘤上有較高的表現;另外在癌症基因庫的比對也顯示,BCAS2 mRNA表現量與前列腺癌患者存活率呈現正相關。綜合我們的研究成果,BCAS2經由與NBS1結合以協助雙股DNA斷裂修復機制,並促進前列腺癌的惡化進展。 | zh_TW |
dc.description.abstract | Breast cancer amplified sequence 2 (BCAS2) plays crucial roles in regulating pre-mRNA splicing, spindle formation during mitosis, and androgen receptor transcription. Previous studies suggest that BCAS2 is involved in DNA repairs, but the details and mechanisms remain to be characterized. We provide evidence here to show that BCAS2 expression protected human prostate cancer cells from the DNA damage of ionizing radiation (IR). To support the results, we also demonstrate that dBCAS2 alleviated IR-induced cell apoptosis in Drosophila wing discs. Mechanistically, BCAS2 was able to enhance the in vitro and in vivo non-homologous end joint (NHEJ) efficiency in double-strand breaks (DSBs) repairs; in parallel, BCAS2 upregulated the homologous recombination (HR) ability during DSBs repairs. Furthermore, we prove that through its N-terminus domain, BCAS2 directly interacted with both the N- and C-terminal domains of NBS1, an indispensable component of the DNA repair/checkpoint complex MRE11-RAD50-NBS1 (MRN). Thus, BCAS2 may positively regulate DNA repairs through facilitating NBS1 recruitment to DSBs. Finally, we found that the expression levels of BCAS2 protein correlated well with that of β-catenin and high expression of BCAS2 was found more frequently in higher-stage human prostate cancer tissues. In addition, the survival analysis showed that high levels of BCAS2 mRNA in PCa tissues were significantly correlated with shorter survival in patients with PCa. Together, our results demonstrate that BCAS2 participates in more than one pathway of DSBs repairs through interaction with NBS1, and may possibly affect prostate cancer progression. | en |
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dc.description.tableofcontents | 致謝.....Ⅰ 中文摘要.....Ⅱ ABSTRACT.....Ⅲ CONTENTS.....Ⅴ CHAPTER 1 INTRODUCTION.....1 1.1 The background of DNA double-strand breaks.....1 1.2 The role of NBS1 in the DNA double-strand break repair.....2 1.3 The characteristic of BCAS2 and splicing.....4 1.4 DNA repair-related functions of PSO4 complex.....5 1.5 Investigations of BCAS2 and its role in physiology.....6 1.6 Replication protein A in regulation of DDR.....8 1.7 Wnt/β-catenin signaling in homeostasis.....9 1.8 BCAS2 serving as a therapeutic agent in cancer therapy.....10 1.9 Aim of this study.....11 CHAPTER 2 MATERIALS AND METHODS.....14 2.1 Cell culture.....14 2.2 Lentiviral particle preparation and infection.....14 2.3 Quantitative real-time PCR.....15 2.4 Cell cycle analysis.....15 2.5 Western blotting.....16 2.6 Immunofluorescence microscopy.....16 2.7 Colocalisation study and confocal microscopy.....17 2.8 Recombinant protein purification and in vitro pull down.....18 2.9 In vitro NHEJ assay.....18 2.10 In vivo NHEJ assay.....19 2.11 Homologous recombination assay.....19 2.12 Immunohistochemistry and scores of protein expressions.....20 2.13 Statistics.....21 CHAPTER 3 RESULTS.....23 3.1 BCAS2 enhances the efficiency of DNA repair after ionizing radiation-induced DNA damage, and reduces the cell death in human PCa cells treated with DSB-causing chemotherapeutic drugs.....23 3.2 Drosophila BCAS2 (dBCAS2) alleviates IR-induced cell apoptosis in Drosophila wing discs in a p53-independent manner.....25 3.3 BCAS2 enhances in vitro and in vivo NHEJ efficiency in DSB repair.....26 3.4 BCAS2 upregulates the efficiency of homologous recombination during DSB repair.....28 3.5 BCAS2 directly interacts with NBS1 through the N-terminus of BCAS2, which is also required for enhancing the efficiency of HR.....29 3.6 BCAS2 regulates DNA repair by facilitating NBS1 recruitment to DSBs.....33 3.7 BCAS2 expression increased in aggressive human PCa samples, correlated with β-catenin and NBS1 expression levels, and it was associated with shorter survival in PCa patients.....33 CHAPTER 4 DISCUSSION.....36 4.1 BCAS2 participates both in NHEJ and HR.....36 4.2 The mechanism BCAS2 regulates the MRN complex activities.....38 4.3 BCAS2 serves as a prostate cancer biomarker.....41 4.4 BCAS2 has its role in embryonic development and homeostasis.....42 CHAPTER 5 CONCLUSION.....48 CHAPTER 6 FIGURES.....49 6.1 Figure 1. Knockdown of BCAS2 expression increased IR-induced damage in LNCaP human prostate carcinoma cells.....50 6.2 Figure 2. Knockdown of BCAS2 expression increased IR-induced damage in PC-3 human prostate carcinoma cells.....51 6.3 Figure 3. Increased BCAS2 expression mitigated IR-induced damage in LNCaP cells.....52 6.4 Figure 4. Increased BCAS2 expression mitigated IR-induced damage in PC-3 cells.....53 6.5 Figure 5. BCAS2 expression alleviated the severity of IR-induced apoptosis in Drosophila wing disc tissues.....54 6.6 Figure 6. BCAS2 positively regulated DSBs repair by enhancing in vitro NHEJ activities.....56 6.7 Figure 7. The expression level of BCAS2 was positively correlated with in vivo NHEJ ability during DSBs repair.....57 6.8 Figure 8. BCAS2 upregulated HR activity.....58 6.9 Figure 9. Validation of interaction between BCAS2 and NBS1 and identification of the NBS1-interacting domain in BCAS2.....59 6.10 Figure 10. Evaluation of the colocalisation status of BCAS2 and NBS1 in U2OS cells.....61 6.11 Figure 11. The percentages of cells with RPA2-pS4/8-positive foci during a time course after irradiation or without irradiation.....63 6.12 Figure 12. Identification of the NBS1-binding domain of BCAS2 and its significance in HR and NHEJ.....64 6.13 Figure 13. Mapping for BCAS2-interacting domain in NBS1.....66 6.14 Figure 14. Depletion of BCAS2 reduced NBS1-related DSBs repair activities.....67 6.15 Figure 15. Knockdown of BCAS2 reduced DNA repair-associated NBS1 recruitment to DSBs.....68 6.16 Figure 16. Higher expression of BCAS2 was detected in more aggressive human PCa and was associated with the expression of β-catenin.....69 6.17 Figure 17. The survival analysis showed that high levels of BCAS2 mRNA in PCa tissues were significantly correlated with shorter survival in patients with PCa.....71 6.18 Figure 18. Schematic diagram of BCAS2 function in DNA double-strand breaks repairs.....73 CHAPTER 7 SUPPLEMENTARY DATA.....74 7.1 Figure S1. Downregulation of BCAS2 repressed the efficiency of repair of double strand DNA breaks (DSBs) involving RPA2-pS4/8 recruitment.....75 7.2 Figure S2. Analyze BCAS2-interacting proteins in LNCaP nuclear extracts.....76 7.3 Figure S3. The list of antibodies used in this study.....78 7.4 Figure S4. The list of cloning primers used in this study.....79 7.5 Figure S5. Original x-film pictures used in Fig1-4.....80 7.6 Figure S6. Original x-film pictures used in Fig6-8.....81 7.7 Figure S7. Original x-film pictures used in Fig9 and Fig12.....82 7.8 Figure S8. Original x-film pictures used in Fig13 and Fig.9.....83 CHAPTER 8 REFERENCE.....84 | |
dc.language.iso | en | |
dc.title | "BCAS2,前列腺癌大量表現的蛋白質,可與NBS1結合以促進雙股DNA斷裂修復之研究" | zh_TW |
dc.title | BCAS2, a protein enriched in advanced prostate cancer, interacts with NBS1 to enhance DNA double-strand break repair | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 黃祥博(Hsiang-Po Huang) | |
dc.contributor.oralexamcommittee | 謝小燕(Sheau-Yann Shieh),李明學(Ming-Shyue Lee),詹世鵬(Shih-Peng Chan) | |
dc.subject.keyword | BCAS2,NBS1,DNA雙股斷裂,非同源末端连接,同源重组修復,前列腺癌, | zh_TW |
dc.subject.keyword | BCAS2,NBS1,DNA double-strand breaks,non-homologous end joint,homologous recombination,prostate cancer, | en |
dc.relation.page | 92 | |
dc.identifier.doi | 10.6342/NTU202100595 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2021-02-08 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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