Please use this identifier to cite or link to this item:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76509Full metadata record
| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 宋麗英(Li-Ying Sung) | |
| dc.contributor.author | Li-Kuang Tsai | en |
| dc.contributor.author | 蔡立廣 | zh_TW |
| dc.date.accessioned | 2021-07-09T15:53:29Z | - |
| dc.date.available | 2022-08-26 | |
| dc.date.copyright | 2019-08-26 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-13 | |
| dc.identifier.citation | REFERENCES
Aguado, T., F. J. Gutierrez, E. Aix, R. P. Schneider, G. Giovinazzo, M. A. Blasco, and I. Flores. 2017. Telomere Length Defines the Cardiomyocyte Differentiation Potency of Mouse Induced Pluripotent Stem Cells. Stem Cells 35(2):362-373. doi: 10.1002/stem.2497 Akiyama, T., L. Xin, M. Oda, A. A. Sharov, M. Amano, Y. Piao, J. S. Cadet, D. B. Dudekula, Y. Qian, W. Wang, S. B. Ko, and M. S. Ko. 2015. Transient bursts of Zscan4 expression are accompanied by the rapid derepression of heterochromatin in mouse embryonic stem cells. DNA Res 22(5):307-318. doi: 10.1093/dnares/dsv013 Allsopp, R. C., E. Chang, M. Kashefi-Aazam, E. I. Rogaev, M. A. Piatyszek, J. W. Shay, and C. B. Harley. 1995. Telomere shortening is associated with cell division in vitro and in vivo. Exp Cell Res 220(1):194-200. doi: 10.1006/excr.1995.1306 Amano, T., T. Hirata, G. Falco, M. Monti, L. V. Sharova, M. Amano, S. Sheer, H. G. Hoang, Y. Piao, C. A. Stagg, K. Yamamizu, T. Akiyama, and M. S. Ko. 2013. Zscan4 restores the developmental potency of embryonic stem cells. Nat Commun 4:1966. doi: 10.1038/ncomms2966 Armanios, M., and E. H. Blackburn. 2012. The telomere syndromes. Nat Rev Genet 13(10):693-704. doi: 10.1038/nrg3246 Arora, R., and C. M. Azzalin. 2015. Telomere elongation chooses TERRA ALTernatives. RNA Biol 12(9):938-941. doi: 10.1080/15476286.2015.1065374 Audebert, M., B. Salles, and P. Calsou. 2004. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem 279(53):55117-55126. doi: 10.1074/jbc.M404524200 Baltimore, D., and D. Smoler. 1971. Primer requirement and template specificity of the DNA polymerase of RNA tumor viruses. Proc Natl Acad Sci U S A 68(7):1507-1511. doi: 10.1073/pnas.68.7.1507 Blasco, M. A., H. W. Lee, M. P. Hande, E. Samper, P. M. Lansdorp, R. A. DePinho, and C. W. Greider. 1997. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91(1):25-34. Boesten, D. M., J. M. de Vos-Houben, L. Timmermans, G. J. den Hartog, A. Bast, and G. J. Hageman. 2013. Accelerated aging during chronic oxidative stress: a role for PARP-1. Oxid Med Cell Longev 2013:680414. doi: 10.1155/2013/680414 Boland, M. J., K. L. Nazor, and J. F. Loring. 2014. Epigenetic regulation of pluripotency and differentiation. Circ Res 115(2):311-324. doi: 10.1161/CIRCRESAHA.115.301517 Bryan, T. M., A. Englezou, L. Dalla-Pozza, M. A. Dunham, and R. R. Reddel. 1997. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med 3(11):1271-1274. Bryan, T. M., A. Englezou, J. Gupta, S. Bacchetti, and R. R. Reddel. 1995. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14(17):4240-4248. Burchett, K. M., A. Etekpo, S. K. Batra, Y. Yan, and M. M. Ouellette. 2017. Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells. Oncotarget 8(48):83754-83767. doi: 10.18632/oncotarget.19410 Cepeda, V., M. A. Fuertes, J. Castilla, C. Alonso, C. Quevedo, M. Soto, and J. M. Perez. 2006. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors in cancer chemotherapy. Recent Pat Anticancer Drug Discov 1(1):39-53. Cesare, A. J., and R. R. Reddel. 2010. Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet 11(5):319-330. doi: 10.1038/nrg2763 Chang, W. F., Y. H. Wu, J. Xu, and L. Y. Sung. 2019. Compromised Chondrocyte Differentiation Capacity in TERC Knockout Mouse Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer. Int J Mol Sci 20(5)doi: 10.3390/ijms20051236 Cheng, Q., N. Barboule, P. Frit, D. Gomez, O. Bombarde, B. Couderc, G. S. Ren, B. Salles, and P. Calsou. 2011. Ku counteracts mobilization of PARP1 and MRN in chromatin damaged with DNA double-strand breaks. Nucleic Acids Res 39(22):9605-9619. doi: 10.1093/nar/gkr656 Chiou, S. H., B. H. Jiang, Y. L. Yu, S. J. Chou, P. H. Tsai, W. C. Chang, L. K. Chen, L. H. Chen, Y. Chien, and G. Y. Chiou. 2013. Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc. J Exp Med 210(1):85-98. doi: 10.1084/jem.20121044 d'Adda di Fagagna, F., M. P. Hande, W. M. Tong, P. M. Lansdorp, Z. Q. Wang, and S. P. Jackson. 1999. Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability. Nat Genet 23(1):76-80. doi: 10.1038/12680 Dan, J., M. Li, J. Yang, J. Li, M. Okuka, X. Ye, and L. Liu. 2013. Roles for Tbx3 in regulation of two-cell state and telomere elongation in mouse ES cells. Sci Rep 3:3492. doi: 10.1038/srep03492 Dan, J., Y. Liu, N. Liu, M. Chiourea, M. Okuka, T. Wu, X. Ye, C. Mou, L. Wang, L. Wang, Y. Yin, J. Yuan, B. Zuo, F. Wang, Z. Li, X. Pan, Z. Yin, L. Chen, D. L. Keefe, S. Gagos, A. Xiao, and L. Liu. 2014. Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing. Dev Cell 29(1):7-19. doi: 10.1016/j.devcel.2014.03.004 Dan, J., P. Rousseau, S. Hardikar, N. Veland, J. Wong, C. Autexier, and T. Chen. 2017. Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells. Cell Rep 20(8):1936-1949. doi: 10.1016/j.celrep.2017.07.070 Dan, J., J. Yang, Y. Liu, A. Xiao, and L. Liu. 2015. Roles for Histone Acetylation in Regulation of Telomere Elongation and Two-cell State in Mouse ES Cells. J Cell Physiol 230(10):2337-2344. doi: 10.1002/jcp.24980 Denchi, E. L., and T. de Lange. 2007. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448(7157):1068-1071. doi: 10.1038/nature06065 Doksani, Y., and T. de Lange. 2016. Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining. Cell Rep 17(6):1646-1656. doi: 10.1016/j.celrep.2016.10.008 Eckersley-Maslin, M. A., V. Svensson, C. Krueger, T. M. Stubbs, P. Giehr, F. Krueger, R. J. Miragaia, C. Kyriakopoulos, R. V. Berrens, I. Milagre, J. Walter, S. A. Teichmann, and W. Reik. 2016. MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs. Cell Rep 17(1):179-192. doi: 10.1016/j.celrep.2016.08.087 Edelstein, L. C., and T. Collins. 2005. The SCAN domain family of zinc finger transcription factors. Gene 359:1-17. doi: 10.1016/j.gene.2005.06.022 Falco, G., S. L. Lee, I. Stanghellini, U. C. Bassey, T. Hamatani, and M. S. Ko. 2007. Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biol 307(2):539-550. doi: 10.1016/j.ydbio.2007.05.003 Ferron, S., H. Mira, S. Franco, M. Cano-Jaimez, E. Bellmunt, C. Ramirez, I. Farinas, and M. A. Blasco. 2004. Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131(16):4059-4070. doi: 10.1242/dev.01215 Frit, P., N. Barboule, Y. Yuan, D. Gomez, and P. Calsou. 2014. Alternative end-joining pathway(s): bricolage at DNA breaks. DNA Repair (Amst) 17:81-97. doi: 10.1016/j.dnarep.2014.02.007 Gao, F., S. W. Kwon, Y. Zhao, and Y. Jin. 2009. PARP1 poly(ADP-ribosyl)ates Sox2 to control Sox2 protein levels and FGF4 expression during embryonic stem cell differentiation. J Biol Chem 284(33):22263-22273. doi: 10.1074/jbc.M109.033118 Gocha, A. R., J. Harris, and J. Groden. 2013. Alternative mechanisms of telomere lengthening: permissive mutations, DNA repair proteins and tumorigenic progression. Mutat Res 743-744:142-150. doi: 10.1016/j.mrfmmm.2012.11.006 Gomez, M., J. Wu, V. Schreiber, J. Dunlap, F. Dantzer, Y. Wang, and Y. Liu. 2006. PARP1 Is a TRF2-associated poly(ADP-ribose)polymerase and protects eroded telomeres. Mol Biol Cell 17(4):1686-1696. doi: 10.1091/mbc.e05-07-0672 Greider, C. W., and E. H. Blackburn. 1985. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43(2 Pt 1):405-413. Hastings, P. J., J. R. Lupski, S. M. Rosenberg, and G. Ira. 2009. Mechanisms of change in gene copy number. Nat Rev Genet 10(8):551-564. doi: 10.1038/nrg2593 Helleday, T. 2011. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 5(4):387-393. doi: 10.1016/j.molonc.2011.07.001 Hirata, T., T. Amano, Y. Nakatake, M. Amano, Y. Piao, H. G. Hoang, and M. S. Ko. 2012. Zscan4 transiently reactivates early embryonic genes during the generation of induced pluripotent stem cells. Sci Rep 2:208. doi: 10.1038/srep00208 Hsieh, M. H., Y. T. Chen, Y. T. Chen, Y. H. Lee, J. Lu, C. L. Chien, H. F. Chen, H. N. Ho, C. J. Yu, Z. Q. Wang, and S. C. Teng. 2017. PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells. Nucleic Acids Res 45(18):10492-10503. doi: 10.1093/nar/gkx683 Huang, J., F. Wang, M. Okuka, N. Liu, G. Ji, X. Ye, B. Zuo, M. Li, P. Liang, W. W. Ge, J. C. Tsibris, D. L. Keefe, and L. Liu. 2011. Association of telomere length with authentic pluripotency of ES/iPS cells. Cell Res 21(5):779-792. doi: 10.1038/cr.2011.16 Hung, S. S., R. C. Wong, A. A. Sharov, Y. Nakatake, H. Yu, and M. S. Ko. 2013. Repression of global protein synthesis by Eif1a-like genes that are expressed specifically in the two-cell embryos and the transient Zscan4-positive state of embryonic stem cells. DNA Res 20(4):391-402. doi: 10.1093/dnares/dst018 Jiang, B. H., W. Y. Chen, H. Y. Li, Y. Chien, W. C. Chang, P. C. Hsieh, P. Wu, C. Y. Chen, H. Y. Song, C. S. Chien, Y. J. Sung, and S. H. Chiou. 2015. CHD1L Regulated PARP1-Driven Pluripotency and Chromatin Remodeling During the Early-Stage Cell Reprogramming. Stem Cells 33(10):2961-2972. doi: 10.1002/stem.2116 Kosugi, S., M. Hasebe, M. Tomita, and H. Yanagawa. 2009. Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifs. Proc Natl Acad Sci U S A 106(25):10171-10176. doi: 10.1073/pnas.0900604106 Kotter, A., K. Cornils, K. Borgmann, J. Dahm-Daphi, C. Petersen, E. Dikomey, and W. Y. Mansour. 2014. Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells. Mol Oncol 8(8):1616-1625. doi: 10.1016/j.molonc.2014.06.008 Lazzerini-Denchi, E., and A. Sfeir. 2016. Stop pulling my strings - what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol 17(6):364-378. doi: 10.1038/nrm.2016.43 Lee, S. S., C. Bohrson, A. M. Pike, S. J. Wheelan, and C. W. Greider. 2015. ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells. Cell Rep 13(8):1623-1632. doi: 10.1016/j.celrep.2015.10.035 Li, J. S., J. Miralles Fuste, T. Simavorian, C. Bartocci, J. Tsai, J. Karlseder, and E. Lazzerini Denchi. 2017. TZAP: A telomere-associated protein involved in telomere length control. Science 355(6325):638-641. doi: 10.1126/science.aah6752 Lodhi, N., A. V. Kossenkov, and A. V. Tulin. 2014. Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark. Nucleic Acids Res 42(11):7028-7038. doi: 10.1093/nar/gku415 Macfarlan, T. S., W. D. Gifford, S. Driscoll, K. Lettieri, H. M. Rowe, D. Bonanomi, A. Firth, O. Singer, D. Trono, and S. L. Pfaff. 2012. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature 487(7405):57-63. doi: 10.1038/nature11244 McVey, M., and S. E. Lee. 2008. MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet 24(11):529-538. doi: 10.1016/j.tig.2008.08.007 Mehta, A., and J. E. Haber. 2014. Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harb Perspect Biol 6(9):a016428. doi: 10.1101/cshperspect.a016428 Min, J., W. E. Wright, and J. W. Shay. 2017. Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes. Mol Cell Biol 37(20)doi: 10.1128/MCB.00226-17 Nakai-Futatsugi, Y., and H. Niwa. 2016. Zscan4 Is Activated after Telomere Shortening in Mouse Embryonic Stem Cells. Stem Cell Reports 6(4):483-495. doi: 10.1016/j.stemcr.2016.02.010 Nishiyama, A., L. Xin, A. A. Sharov, M. Thomas, G. Mowrer, E. Meyers, Y. Piao, S. Mehta, S. Yee, Y. Nakatake, C. Stagg, L. Sharova, L. S. Correa-Cerro, U. Bassey, H. Hoang, E. Kim, R. Tapnio, Y. Qian, D. Dudekula, M. Zalzman, M. Li, G. Falco, H. T. Yang, S. L. Lee, M. Monti, I. Stanghellini, M. N. Islam, R. Nagaraja, I. Goldberg, W. Wang, D. L. Longo, D. Schlessinger, and M. S. Ko. 2009. Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. Cell Stem Cell 5(4):420-433. doi: 10.1016/j.stem.2009.07.012 Okashita, N., Y. Suwa, O. Nishimura, N. Sakashita, M. Kadota, G. Nagamatsu, M. Kawaguchi, H. Kashida, A. Nakajima, M. Tachibana, and Y. Seki. 2016. PRDM14 Drives OCT3/4 Recruitment via Active Demethylation in the Transition from Primed to Naive Pluripotency. Stem Cell Reports 7(6):1072-1086. doi: 10.1016/j.stemcr.2016.10.007 Ottaviani, D., M. LeCain, and D. Sheer. 2014. The role of microhomology in genomic structural variation. Trends Genet 30(3):85-94. doi: 10.1016/j.tig.2014.01.001 Piskunova, T. S., M. N. Yurova, A. I. Ovsyannikov, A. V. Semenchenko, M. A. Zabezhinski, I. G. Popovich, Z. Q. Wang, and V. N. Anisimov. 2008. Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice. Curr Gerontol Geriatr Res:754190. doi: 10.1155/2008/754190 Roper, S. J., S. Chrysanthou, C. E. Senner, A. Sienerth, S. Gnan, A. Murray, M. Masutani, P. Latos, and M. Hemberger. 2014. ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells. Nucleic Acids Res 42(14):8914-8927. doi: 10.1093/nar/gku591 Rouleau, M., A. Patel, M. J. Hendzel, S. H. Kaufmann, and G. G. Poirier. 2010. PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10(4):293-301. doi: 10.1038/nrc2812 Sarek, G., P. Marzec, P. Margalef, and S. J. Boulton. 2015. Molecular basis of telomere dysfunction in human genetic diseases. Nat Struct Mol Biol 22(11):867-874. doi: 10.1038/nsmb.3093 Sharma, V., S. N. Pandey, H. Khawaja, K. J. Brown, Y. Hathout, and Y. W. Chen. 2016. PARP1 Differentially Interacts with Promoter region of DUX4 Gene in FSHD Myoblasts. J Genet Syndr Gene Ther 7(4)doi: 10.4172/2157-7412.1000303 Shay, J. W., and S. Bacchetti. 1997. A survey of telomerase activity in human cancer. Eur J Cancer 33(5):787-791. doi: 10.1016/S0959-8049(97)00062-2 Sperka, T., Z. Song, Y. Morita, K. Nalapareddy, L. M. Guachalla, A. Lechel, Y. Begus-Nahrmann, M. D. Burkhalter, M. Mach, F. Schlaudraff, B. Liss, Z. Ju, M. R. Speicher, and K. L. Rudolph. 2011. Puma and p21 represent cooperating checkpoints limiting self-renewal and chromosomal instability of somatic stem cells in response to telomere dysfunction. Nat Cell Biol 14(1):73-79. doi: 10.1038/ncb2388 Storm, M. P., B. Kumpfmueller, H. K. Bone, M. Buchholz, Y. Sanchez Ripoll, J. B. Chaudhuri, H. Niwa, D. Tosh, and M. J. Welham. 2014. Zscan4 is regulated by PI3-kinase and DNA-damaging agents and directly interacts with the transcriptional repressors LSD1 and CtBP2 in mouse embryonic stem cells. PLoS One 9(3):e89821. doi: 10.1371/journal.pone.0089821 Sung, L. Y., W. F. Chang, Q. Zhang, C. C. Liu, J. Y. Liou, C. C. Chang, H. Ou-Yang, R. Guo, H. Fu, W. T. K. Cheng, S. T. Ding, C. M. Chen, M. Okuka, D. L. Keefe, Y. E. Chen, L. Liu, and J. Xu. 2014. Telomere elongation and naive pluripotent stem cells achieved from telomerase haplo-insufficient cells by somatic cell nuclear transfer. Cell Rep 9(5):1603-1609. doi: 10.1016/j.celrep.2014.10.052 Takai, H., R. C. Wang, K. K. Takai, H. Yang, and T. de Lange. 2007. Tel2 regulates the stability of PI3K-related protein kinases. Cell 131(7):1248-1259. doi: 10.1016/j.cell.2007.10.052 Tardat, M., and J. Dejardin. 2018. Telomere chromatin establishment and its maintenance during mammalian development. Chromosoma 127(1):3-18. doi: 10.1007/s00412-017-0656-3 Ulaner, G. A., J. F. Hu, T. H. Vu, L. C. Giudice, and A. R. Hoffman. 1998. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res 58(18):4168-4172. Vilas, C. K., L. E. Emery, E. L. Denchi, and K. M. Miller. 2018. Caught with One's Zinc Fingers in the Genome Integrity Cookie Jar. Trends Genet 34(4):313-325. doi: 10.1016/j.tig.2017.12.011 Williams, A. J., S. C. Blacklow, and T. Collins. 1999. The zinc finger-associated SCAN box is a conserved oligomerization domain. Mol Cell Biol 19(12):8526-8535. doi: 10.1128/mcb.19.12.8526 Yang, G., C. Liu, S. H. Chen, M. A. Kassab, J. D. Hoff, N. G. Walter, and X. Yu. 2018. Super-resolution imaging identifies PARP1 and the Ku complex acting as DNA double-strand break sensors. Nucleic Acids Res 46(7):3446-3457. doi: 10.1093/nar/gky088 Zalzman, M., G. Falco, L. V. Sharova, A. Nishiyama, M. Thomas, S. L. Lee, C. A. Stagg, H. G. Hoang, H. T. Yang, F. E. Indig, R. P. Wersto, and M. S. Ko. 2010. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature 464(7290):858-863. doi: 10.1038/nature08882 Zhang, J. M., T. Yadav, J. Ouyang, L. Lan, and L. Zou. 2019. Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways. Cell Rep 26(4):955-968 e953. doi: 10.1016/j.celrep.2018.12.102 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76509 | - |
| dc.description.abstract | Zinc finger and SCAN domain containing 4 (Zscan4)為大量表現於二細胞時期鼠胚之基因。在體外培養中僅約1-5%的胚幹細胞可表達此基因。Zscan4之主要功能包含維持基因組穩定與調控端粒長度之動態平衡等，並可藉由非端粒酶之同源重組之方式延長端粒長度。然而，Zscan4延長端粒之分子機制至今仍未明瞭。透過免疫沈澱串聯質譜儀的方式，poly [ADP-ribose] polymerase 1 (PARP1)被預測為ZSCAN4潛在的結合蛋白之一，具有酵素活性，可將NAD+上之ADP-ribose接至目標蛋白上。過去研究顯示PARP1為偵測DNA斷裂並參與在DNA修復之重要蛋白；更重要的是，剔除Parp1基因後，會導致小鼠端粒變短且提早老化。因此，本研究之目的為藉由探討ZSCAN4與其潛在結合蛋白PARP1之間的交互作用，以期進一步了解ZSCAN4延長端粒之機制。在本研究中，首先產製Flag-Zscan4與Ha-Parp1之重組質體，透過FLAG與HA抗體分別進行共同免疫沈澱，確認PARP1為一ZSCAN4之結合蛋白。接著，根據不同蛋白結構域將Zscan4與Parp1分別截斷為三個部分，包括Zscan4的SCAN、Linker sequence及Zinc finger （ZF) domain；與Parp1之DNA binding (DB)、Automodification (AM)及Catalytic domain，更進一步發現ZSCAN4以SCAN domain與PARP1之DB domain與AM domain結合，且ZSCAN4也會以ZF domain與PARP1之AM domain結合。為了解PARP1在ZSCAN4延長端粒中扮演之角色，進一步產製了ZSCAN4過表達之胚幹細胞株，並發現相較於控制組細胞，此細胞株之增殖速率較慢且端粒長度有較長的特性。接著，在施予PARP的抑制劑處理後，控制組胚幹細胞中發現端粒有顯著延長的現象；然在ZSCAN4過表達的胚幹細胞株中則觀察到細胞喪失其原本端粒長度較長的特性，顯示PARP1可能在ZSCAN4延長端粒的機制中扮演著雙重的角色。後續以短髮夾RNA降低Parp1的表現量後，觀察到端粒調控相關之基因被激活，Zscan4的表現量有顯著的提升，且端粒有延長的現象，進一步證實了PARP1具有抑制Zscan4表現的能力。最後透過端粒酶半缺失（Terc+/-）之核移殖胚幹細胞（ntESCs）模擬端粒綜合症的患者，施予PARP的抑制劑，期能補救其端粒較短之缺陷。結果顯示，試驗之三株Terc+/- ntESCs中，其中一株ntESCs有顯著延長端粒的效果。綜上所述，本研究驗證PARP1為一與ZSCAN4結合之蛋白，並進一步揭露其交互作用之蛋白功能域；另也發現PARP1在調控ZSCAN4與端粒長度上可能扮演著雙重的角色，然而Zscan4如何參與延長端粒更詳盡之分子機制仍待更進一步的實驗釐清。由於Zscan4為藉由非端粒酶途徑調控端粒長度之重要蛋白，若能深入探討Zscan4延長端粒之分子機制，盼能為端粒綜合症患者提供有效治療之策略或方向。 | zh_TW |
| dc.description.abstract | Zinc finger and SCAN domain containing 4 (Zscan4) is a gene that expressed in 2-cell stage embryos and sporadically in a subpopulation of embryonic stem cells (ESCs). Zscan4 participates in the regulation of telomere homeostasis and genomic stability. However, the detailed mechanism of Zscan4 involved in telomere elongation is still unclear. Poly [ADP-ribose] polymerase 1 (PARP1) is known to sense DNA damage and activate several DNA repair pathways. The objective of this study is to investigate the mechanisms of PARP1 interacts with ZSCAN4 and participates in telomere regulation. By serial immunoprecipitations, our data showed that PARP1 not only interacted with SCAN domain of ZSCAN4 through DNA binding domain and auto-modification domain but also interacted with zinc finger domain of ZSCAN4 by auto-modification domain. To investigate whether PARP1 is associated with ZSCAN4 in telomere homeostasis, Zscan4 over-expressed ESCs (OEZ4 ESCs) were generated. We found that OEZ4 ESCs show slower proliferation rate and significantly longer telomere length compared to the vector control. Moreover, inhibition of PARP1 activity by treating 3-aminobenzamide (3-AB), the PARP inhibitor, led to shorten telomeres in OEZ4 ESCs, indicating PARP1 may play dual roles to interact with Zscan4 and participates in telomere regulation. Next, knockdown Parp1 by shRNA in ESCs showed elongation of telomere length and activation of genes involved in telomere regulation, suggesting PARP1 regulates telomere homeostasis. Lastly, treating 3-AB in Terc+/- ntESCs, which mimic the telomere syndrome patient, we further reveal that shorten telomeres has been elongated. In conclusion, this study uncovers PARP1 as a ZSCAN4-associated protein and participates in telomere regulation, and provides novel insights on the molecular interaction between DNA damage and telomere regulation. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-09T15:53:29Z (GMT). No. of bitstreams: 1 ntu-108-R06642002-1.pdf: 10646811 bytes, checksum: d0c4250230bcf3c36cd7c4f694adbdd4 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 誌謝 1
中文摘要 2 ABSTRACT 3 CONTENTS 4 LIST OF FIGURES 6 LIST OF TABLES 7 ABBREVIATIONS 8 CHARTER I: GENERAL INTRODUCTION AND LITERATURE REVIEW 10 1. GENERAL INTRODUCTION 11 2. LITERATURE REVIEW 13 2-1. Functions of telomere 13 2-2. Ways to elongate telomere length 14 2-3. Zinc finger and SCAN domain containing 4 (ZSCAN4) 16 2-4. Poly (ADP-ribose) polymerase 1 (PARP1) 18 2-5. Effect of telomere length on stem cells potency 20 3. PERSPECTIVE 21 CHAPTER II: VERIFICATION OF PARP1 INTERACTS WITH ZSCAN4 23 1. BACKGROUND 24 2. MATERIALS AND METHODS 26 3. RESULTS 32 3-1. Localization of ZSCAN4, PARP1 and telomere in somatic cells and ESCs 32 3-2. PARP1 is a ZSCAN4-interaction protein 34 3-3. ZSCAN4 interacted with PARP1 through SCAN domain and Zinc finger domain 34 3-4. PARP1 interacted with ZSCAN4 through DNA binding domain and automodification domain 35 3-5. SCAN domain of ZSCAN4 interacts with both DBD and AMD of PARP1 while ZF of ZSCAN4 binding with only AMD of PARP1 36 4. DISCUSSION 46 CHAPTER III: FUNCTION OF PARP1 INTERACTS WITH ZSCAN4 IN TELOMERE HOMEOSTASIS 49 1. BACKGROUND 50 2. MATERIALS AND METHODS 52 3. RESULTS 59 3-1. Zscan4 over-expressed ESCs shows slower proliferative rate and longer telomere length 59 3-2. Inhibition of PARP1 affects telomere homeostasis 60 3-3. Knockdown of Parp1 leads to Zscan4 derepression and telomere elongation 60 3-4. PARP1 inhibition in Terc+/- ntESCs activated telomere regulation genes 62 4. DISCUSSION 73 GENERAL DISCUSSION 76 CONCLUSIONS 78 REFERENCES 80 | |
| dc.language.iso | en | |
| dc.title | PARP1與ZSCAN4交互作用對端粒長度調節之探討 | zh_TW |
| dc.title | The Interaction Between PARP1 and ZSCAN4 and Their Roles on Telomere Regulation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 朱志成(Jyh-Cherng Ju),楊尚訓(Shang-Hsun Yang),李宣書(Hsuan-Shu Lee),林劭品(Shau-Ping Lin) | |
| dc.subject.keyword | ZSCAN4,PARP1,端粒,胚幹細胞, | zh_TW |
| dc.subject.keyword | ZSCAN4,PARP1,telomere,embryonic stem cells, | en |
| dc.relation.page | 91 | |
| dc.identifier.doi | 10.6342/NTU201903408 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2019-08-14 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 生物科技研究所 | zh_TW |
| dc.date.embargo-lift | 2022-08-26 | - |
| Appears in Collections: | 生物科技研究所 | |
Files in This Item:
| File | Size | Format | |
|---|---|---|---|
| ntu-108-R06642002-1.pdf | 10.4 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.