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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳青錫(Ching-Shyi Wu) | |
| dc.contributor.author | Pei-Jung Yen | en |
| dc.contributor.author | 嚴珮容 | zh_TW |
| dc.date.accessioned | 2022-11-25T07:30:52Z | - |
| dc.date.available | 2026-01-01 | |
| dc.date.copyright | 2021-11-09 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-09-23 | |
| dc.identifier.citation | Khanna, K. K. Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nature genetics 27, 247-254, (2001). Jackson, S. P. Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071-1078, (2009). Hoeijmakers, J. H. DNA damage, aging, and cancer. The New England journal of medicine 361, 1475-1485, (2009). Ward, J. F. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Progress in nucleic acid research and molecular biology 35, 95-125, (1988). Ciccia, A. Elledge, S. J. The DNA damage response: making it safe to play with knives. Molecular cell 40, 179-204, (2010). Harper, J. W. Elledge, S. J. The DNA damage response: ten years after. Molecular cell 28, 739-745, (2007). Harrison, J. C. Haber, J. E. Surviving the breakup: the DNA damage checkpoint. Annual review of genetics 40, 209-235, (2006). Cimprich, K. A. Cortez, D. ATR: an essential regulator of genome integrity. Nature reviews. Molecular cell biology 9, 616-627, (2008). Maréchal, A. et al. PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Molecular cell 53, 235-246, (2014). Bartek, J. Lukas, J. DNA damage checkpoints: from initiation to recovery or adaptation. Current opinion in cell biology 19, 238-245, (2007). Liu, E. et al. The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted. The Journal of cell biology 179, 643-657, (2007). Huen, M. S. Chen, J. The DNA damage response pathways: at the crossroad of protein modifications. Cell research 18, 8-16, (2008). Moynahan, M. E. Jasin, M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nature reviews. Molecular cell biology 11, 196-207, (2010). Lieber, M. R. NHEJ and its backup pathways in chromosomal translocations. Nature structural molecular biology 17, 393-395, (2010). Lee, J. H. Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science (New York, N.Y.) 308, 551-554, (2005). Buisson, R. et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nature structural molecular biology 17, 1247-1254, (2010). Chang, H. H. Y., Pannunzio, N. R., Adachi, N. Lieber, M. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nature reviews. Molecular cell biology 18, 495-506, (2017). Chang, H. M. Yeh, E. T. H. SUMO: From Bench to Bedside. Physiological reviews 100, 1599-1619, (2020). Yeh, E. T. SUMOylation and De-SUMOylation: wrestling with life's processes. The Journal of biological chemistry 284, 8223-8227, (2009). Flotho, A. Melchior, F. Sumoylation: a regulatory protein modification in health and disease. Annual review of biochemistry 82, 357-385, (2013). Vertegaal, A. C. SUMO chains: polymeric signals. Biochemical Society transactions 38, 46-49, (2010). Gareau, J. R. Lima, C. D. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nature reviews. Molecular cell biology 11, 861-871, (2010). Wu, C. S. et al. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway. Genes development 28, 1472-1484, (2014). Dou, H., Huang, C., Singh, M., Carpenter, P. B. Yeh, E. T. Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex. Molecular cell 39, 333-345, (2010). Pichler, A., Fatouros, C., Lee, H. Eisenhardt, N. SUMO conjugation - a mechanistic view. Biomolecular concepts 8, 13-36, (2017). Galanty, Y. et al. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462, 935-939, (2009). Zhou, L. et al. SUMOylation stabilizes hSSB1 and enhances the recruitment of NBS1 to DNA damage sites. Signal transduction and targeted therapy 5, 80, (2020). Wu, C. S. Zou, L. The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation. The Journal of biological chemistry 291, 279-290, (2016). Liu, S. et al. PIAS3 promotes homology-directed repair and distal non-homologous end joining. Oncology letters 6, 1045-1048, (2013). Chung, C. D. et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science (New York, N.Y.) 278, 1803-1805, (1997). Haince, J. F. et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. The Journal of biological chemistry 283, 1197-1208, (2008). Wassing, I. E. Esashi, F. RAD51: Beyond the break. Seminars in cell developmental biology 113, 38-46, (2021). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82428 | - |
| dc.description.abstract | 當細胞受到傷害後會啟動一連串的機制去維持基因的完整性，這些機制稱為DNA損傷反應，簡稱DDR。已經知道ATR-Chk1訊息路徑對DDR很重要。先前的研究發現SUMO E3連接酶PIAS3對於ATR-Chk1訊息路徑的活化是必不可少的，並且也與DNA修復有關。最近的研究也發現具有PIAS3缺陷的癌症通常對標準治療有抵抗力，患者存活率也比較低。因此，在本研究中，我探索PIAS3是如何調控DDR的訊號傳遞，並期待可以找出新的癌症治療方法。ATR-Chk1訊息路徑的活化可以通過在細胞中給予WT或失去E3 SUMO連接酶活性 (SA) 的PIAS3來挽救，但是在細胞存活實驗中顯示具有SA突變的細胞對PARP抑製劑更為敏感。在蛋白質-蛋白質相互作用分析顯示，參與DNA雙鏈斷裂修復和DNA複製的蛋白質，如HIST2H3A、LIG3、MTA1、PARP1、PRP19、RFC1和XRCC5/6，是 PIAS3的相互作用蛋白。透過Co-IP實驗更進一步驗證了PIAS3和PRP19 與 PARP1確實會相互作用。通過UV雷射造成DNA損傷的實驗，我們發現當細胞缺乏PIAS3會影響PRP19聚集到DNA損傷處，但不會影響 PARP1聚集到DNA損傷處。雖然詳細機制仍然在尋找中，但是，我們的結果顯示PIAS3的SUMO E3連接酶活性可能對ATR-Chk1訊息路徑活化並不是關鍵，但是卻對DNA修復很重要。此外，通過UV雷射造成DNA損傷的實驗，我們發現當細胞缺乏PIAS3會影響RAD51聚集到DNA損傷處。綜合我的研究和先前的研究，發現PIAS3缺陷的癌細胞可以被PARP和ATR抑制劑選擇性殺死，為開發針對PIAS3缺陷的癌症的新癌症療法提供了有潛力的方向。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T07:30:52Z (GMT). No. of bitstreams: 1 U0001-1609202111470500.pdf: 6125795 bytes, checksum: 9ccfc2a46a2a5d2194fd0daba97467fb (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 致謝 ----- I Abbreviation ----- II 中文摘要 ----- V Abstract ----- VI Introduction ----- 1 Materials and Methods ----- 7 Results ----- 14 Discussion ----- 19 Figures ----- 22 Tables ----- 41 References ----- 44 | |
| dc.language.iso | en | |
| dc.subject | SUMO E3連接酶 | zh_TW |
| dc.subject | PRP19 | zh_TW |
| dc.subject | DNA損傷反應 | zh_TW |
| dc.subject | 癌症治療 | zh_TW |
| dc.subject | RAD51 | zh_TW |
| dc.subject | 同源修復 | zh_TW |
| dc.subject | SUMO E3 ligase | en |
| dc.subject | Cancer therapy | en |
| dc.subject | Homologous recombination repair | en |
| dc.subject | RAD51 | en |
| dc.subject | PRP19 | en |
| dc.subject | DNA damage response | en |
| dc.title | SUMO E3連接酶PIAS3在DNA損害反應中之角色 | zh_TW |
| dc.title | The Role of SUMO E3 ligase PIAS3 in the DNA Damage Response | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林敬哲(Hsin-Tsai Liu),鄧述諄(Chih-Yang Tseng) | |
| dc.subject.keyword | DNA損傷反應,SUMO E3連接酶,PRP19,RAD51,同源修復,癌症治療, | zh_TW |
| dc.subject.keyword | DNA damage response,SUMO E3 ligase,PRP19,RAD51,Homologous recombination repair,Cancer therapy, | en |
| dc.relation.page | 48 | |
| dc.identifier.doi | 10.6342/NTU202103204 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2021-09-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| dc.date.embargo-lift | 2026-01-01 | - |
| 顯示於系所單位： | 藥理學科所 | |
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