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基因體穩定性與老化分子機制實驗室

  • 維持基因體遺傳物質的穩定性是生物存活及繁衍所必需,當此穩定性被破壞後可能造成個體的不良影響甚至死亡,抑或當隨著年齡增長,個體遺傳物質的變異逐漸累積進而顯現老化的現象。我們研究室對於基因體穩定性及老化的生命現象極感興趣並致力研究其分子機制。我們主要是利用生物化學、遺傳學、超顯微影像方法以及單分子影像技術的層面來著手研究上述的課題。我們主要研究的基因是DNA拓撲異構酶(拓撲酶):在細胞核中諸多重要的生物反應過程都會產生DNA纏繞糾結的拓撲結構,例如遺傳物質的複製、轉錄、重組、修復及染色質的重置。此拓撲結構必須要能被解繫,否則必會阻礙上述生物反應的進行。而生物必需的拓撲可經由股間穿越的方式解決該問題進而調控DNA與染色體的結構與功能。我們除了藉由純化拓撲酶蛋白(種類來源包括人類、果蠅和寄生性超嗜熱型古生菌Nanoarchaeum equitans)來研究其生物化學與生物物理的特性外,還利用非脊椎與脊椎動物模式(果蠅和小鼠)來研究在拓撲酶基因缺失的情況下對個體的影響。除了拓撲酶之外,我們另一個感興趣的對象RecQ4解旋酶,該基因是RecQ解旋酶家族中重要的一員,Rothmund Thomson症候群便肇因於人類RecQ4基因的突變。除了在已知基因做更深入的研究,我們更嘗試去發掘一些具有重要功能但尚未被研究的新穎基因。我們近期在果蠅發現一基因,該基因的突變會導致果蠅生育功能缺失,我們因而將其命名為無後(wuho)。有趣的是我們觀察到無後、RecQ4解旋酶以及拓撲酶基因突變的實驗動物都有顯著壽命縮短的現象,顯示基因體穩定性與老化之間的相關性。我們的目標就在釐清當中的分子機制。

     

     
  • 姓名職稱電話Email備註
    謝道時特聘研究員 兼所長
    黃婉媜博士後研究員
    陳易呈博士後研究員
    劉怡棻博士後研究員
    林仁國 博士後研究員
    張凱為博士後研究員
    帥宏勳研究助理
    吳家翔研究助理
    高佑瑄研究助理
    翁群智研究助理
    鮑昱全研究助理
    林心瀅研究助理
    蔡涵任博士班學生
    蕭意如博士班學生
    艾杰博士班學生
    王桂枝 助理
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    近期代表著作

     

     

    1. Cheng IC, Chen BC, Shuai HH, Chien FC, Chen P, and Hsieh T.-s., 2016, “Wuho Is a New Member in Maintaining Genome Stability through its Interaction with Flap Endonuclease 1.”, PLoS Biol. 14(1): e1002349. doi:10.1371/journal.pbio.1002349
    2. Lin YS, Huang WC, Chen MS, and Hsieh T.-s., 2014, “Toward discovering new anti-cancer agents targeting topoisomerase IIα: A facile screening strategy adaptable to the high throughput platform.”, PLoS ONE. 9(5): e97008.
    3. Chen SH, Plank JL, Willcox S, Griffith JD, and Hsieh T.-s., 2014, “Top3a is required during the convergent migration step of double Holliday junction dissolution.”, PLoS ONE. 9(1): e83582.
    4. Lee SH, Siaw GEL, Willcox S, Griffith JD, and Hsieh T.-s., 2013, “Synthesis and dissolution of hemicatenanes by type IA DNA topoisomerases.”, Proc. Natl. Acad. Sci. USA. 110(38): E3587-94.
    5. Chen, SH., Chan, NL, and Hsieh T.-s., 2013, “New Mechanistic and Functional Insights into DNA topoisomerases.”, Annual Review of Biochem., 82:139-70.
    6. Chen SH, Plank JL, Willcox S., Griffith JD, and Hsieh T.-s., 2012, “Improved methods for creating migratable Holliday junction substrates.” Nucleic Acids Research. 41(5): e60.
    7. Hohl AM, Thompson M, Soshnev AA, Wu J, Morris J, Hsieh T.-s., Wu CT, Geyer PK., 2012, “Restoration of Topoisomerase 2 Function by Complementation of Defective Monomers in Drosophila. Genetics 192, 843-856.
    8. Chen YT, Collins TR, Guan Z, Chen B and Hsieh T.-s., 2012, “Probing Conformational Changes in Human DNA Topoisomerase IIα BY Pulse-Alkylation Mass Spectrometry.” J. Biol. Chem. 287, 25660-8.
    9. Huang J. Yu P. Yuan CT, Ko HC., Tang J., Hsieh T.-s., 2012, “Single-particle studies of the plasmonic fluorescence in gold nanocubes.” Journal of Nanophotonics. 6, 0695021-0695026
    10. Chen SH, Wu CH, Plank JL, and Hsieh T.-s., 2012, “Essential Functions of the C-terminus of Drosophila topoisomerase IIIα in double Holliday junction dissolution.” J. Biol. Chem. 287, 19346-19353 (selected as paper of the Week).
    11. Fasulo B, Koyama C, Yu KR, Homola Em, Hsieh T.-s., Campbell SD, Sullivan W., 2012, “Chk1 and Wee1 Kinases coordinate DNA replication, chromosome condensation and anaphase entry.” Mol Biol Cell. 23, 1047-1057
    12. Lin RK, Zhou N, Lyu YL, Tsai YC, Lu CH, Kerrigan J, Chen YT, Guan Z, Hsieh T.-s., and Liu LF., 2011, Dietary Isothiocyanate-Induced Apoptosis via Thiol Modification of DNA Topoisomerase II.  J Biol Chem. 286, 33591-33600.
    13. Capp C, Qian Y, Sage H, Huber H, Hsieh T.-s., 2010, “Separate and combined biochemical activities of the subunits of a naturally split reverse gyrase.” J Biol Chem. 285, 39637-45.
    14. Wu J, Phatnani HP, Hsieh T.-s. and Greenleaf AL., 2010, “The phosphoCTD-interacting domain of Topoisomerase I.”  Biochem Biophys Res Commun. 397, 117-9.
    15. Capp C, Wu J and Hsieh T.-s., 2010, “RecQ4: the second replicative helicase?”  Crit. Rev Biochem Mol Biol  45, 233-42   
    16. Wu J, Feng L and Hsieh T.-s., 2010, “Drosophila topo IIIα is required for the maintenance of mitochondrial genome and male germ-line stem cells.” Proc. Natl. Acad. Sci. USA  107, 6228-33  
    17. Capp C, Wu J, Hsieh T.-s., 2009, “Drosophila RecQ4 has a 3'-5'DNA helicase activity that is essential for viability.” J Biol Chem. 284, 30845-30852.
    18. Plank JL, and Hsieh T.-s., 2009, “Helicase-appended topoisomerases: new insight into the mechanism of directional strand-transfer.” J Biol Chem. 284, 30737-30741, JBC mini-review.
    19. Collins TR, Hammes GG, Hsieh, T-s., 2009, “Analysis of the eukaryotic topoisomerase II DNA gate: a single-molecule FRET and structural perspective.” Nucleic Acids Res. 37, 712-20.
    20. Collins TR, and Hsieh, T.-s., 2009, “Monitoring the topoisomerase II DNA gate conformational change with fluorescence resonance energy transfer.” Methods in Mol. Biol. 582, 59-70.

     

     

    Book Chapters:

     

    1. Chen S H, Wu J, and Hsieh T.-s., 2012, “Essential functions of topoisomerase IIIα in the nucleus and mitochondria.”, editor(s): Y. Pommier, DNA Topoisomerases and Cancer, pp. 103-117, New York: Springer.
    2. Hsieh T.-s., 2012, “DNA Supercoiling.”, editor(s): Lennarz, William and Lane, M. Daniel, Encyclopedia of Biological Chemistry 2nd Edition, volume 1, pp. 794-797, Elsevier Science. 

     


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    115台北市南港區研究院路二段128號
    Tel: 02-27899515
    Fax: 02-27858059
    icob@gate.sinica.edu.tw
    Copyright © ICOB 2013. All rights reserved. 最佳瀏覽網頁方式請用最新版IE11或其他瀏覽器 /瀏覽人數:941103--
     瀏覽人數:941103