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研究生:曹甯
研究生(外文):Ning Tsao
論文名稱:胞嘧啶核苷酸單磷酸激酶和核苷酸二磷酸激酶3對於DNA修補之貢獻
論文名稱(外文):The Contribution of CMP Kinase and Nucleoside Diphosphate Kinase 3 in DNA Repair
指導教授:張智芬
指導教授(外文):Zee-Fen Chang
口試委員:謝小燕鄧述諄李財坤徐沺
口試日期:2015-06-04
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生物化學暨分子生物學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:98
中文關鍵詞:去氧核醣核苷酸三磷酸(dNTPs)核糖核酸還原酶(RNR)胞嘧啶單磷酸核苷酸激酶(CMPK)核苷酸二磷酸激酶3(NME3)Tip60DNA修補
外文關鍵詞:deoxynucleotide triphosphate (dNTP)ribonucleotide reductase (RNR)CMPKNME3Tip60DNA repair
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DNA在複製及修補時需有足量且平衡的去氧核醣核苷酸三磷酸(dNTPs)供給。其中,核糖核酸還原酶(RNR)為合成dNTP的關鍵酵素,可將核糖核苷酸二磷酸(NDPs)還原成去氧核醣核苷酸二磷酸(dNDPs),同時也是DNA修補時所必須。我的研究則進一步發現胞嘧啶單磷酸核苷酸激酶(CMPK)及核苷酸二磷酸激酶3(NME3)在DNA修補上扮演重要的角色。其中CMPK的功能為合成胞嘧啶核苷酸二磷酸(CDP或dCDP),NME3則為十種核苷酸二磷酸激酶(nucleoside diphosphate kinase)異構體的成員之一,負責將(d)NDP合成為(d)NTP。在無血清培養之下,降低CMPK表現量減緩細胞對UV造成DNA損傷的修補,但在增殖細胞中則否。降低NME3表現量則減緩細胞對阿黴素(doxorubicin)造成DNA損傷的修補。我的研究也進一步發現這兩個酵素皆會透過自身蛋白的N端區域與組蛋白乙醯化酶-Tip60及RNR形成蛋白複合體,而匯集到DNA損傷區域。去除蛋白質N端區域的CMPK及NME3則無法和Tip60形成蛋白複合體,同時也導致在DNA修補能力上的缺陷。因此,我認為多重酵素複合體在DNA損傷處的形成提供一個細胞內局部生成dNTP的方式,使細胞在無血清培養下有效促進DNA的修補。除此之外,NME3在增殖細胞中DNA修補的角色也牽涉到了核醣核苷酸三磷酸(rNTP)的合成。

Cellular supply of deoxynucleoside triphosphates (dNTPs) is crucial for DNA replication and repair. Ribonucleotide reducatse (RNR) is a rate-limiting enzyme for dNTP synthesis required for DNA repair, by reduction of four ribonucleoside diphosphates to generate corresponding dNDPs. In my thesis, the functional importance of UMP/CMP kinase (CMPK), an enzyme catalyzes (d)CDP formation and nucleoside diphosphate kinase 3 (NME3), one of ten isoforms of NME that converts (d)NDPs to (d)NTPs in DNA repair are demonstrated. Knockdown of CMPK delayed DNA repair after UV-irradiation in serum-deprived cells but had no effect on proliferating cells, while knockdown of NME3 declined DNA repair rate after doxorubicin exposure in proliferating cells. In addition, these two enzymes could form a complex with RNR and Tip60, a histone acetyltransferase by their N-terminal regions and recruited to DNA damages sites in a Tip60-depedent manner. The mutants of CMPK and NME3 with their N-terminal sequences deletion to eliminate their interaction with Tip60 also show the functional deficiency in DNA repair as compared to wild-type enzymes. I propose that the site-specific multienzyme complex formation provides a means for local synthesis of dNTPs to facilitate DNA repair in serum-deprived cells, which contain low cellular dNTP supply from cytosol. In addition to Tip60/RNR interaction for dNTPs supply at DNA damage sites, another function of NME3 in proliferating cells for DNA repair may involve the local production of ribonucleoside triphosphates (rNTPs).

口試委員審定書................................................................................................................i
謝誌...................................................................................................................................ii
中文摘要..........................................................................................................................iii
Abstract............................................................................................................................iv
Chapter I. Overview and Rationale
1. De novo synthesis of dNTP in DNA repair....................................................................1
2. The substrates of RNR and the conversion of RNR products to dNTP.........................2
3. Site-specific recruitment or nuclear localization of nucleotide metabolism enzymes for DNA replication and repair..........................................................................................6
4. Rationale........................................................................................................................8
5. Materials and Methods..................................................................................................9
Chapter II. The contribution of CMP kinase to the efficiency of DNA repair
1. Introduction.................................................................................................................17
2. Results.........................................................................................................................19
3. Discussion....................................................................................................................25
4. Table/Figures and Legends..........................................................................................28
Chapter III. Making nucleoside triphosphate by NME3 in DNA repair
1. Introduction.................................................................................................................47
2. Results.........................................................................................................................49
3. Discussion....................................................................................................................58
4. Table/Figures and Legends..........................................................................................60
Perspectives.....................................................................................................................86
References.......................................................................................................................88
Vita/Appendix..................................................................................................................98


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