Title

胸腺嘧啶激酶1參與DNA損傷修復之探討

Translated Titles

Involvement of Thymidine Kinase 1 in DNA repair

DOI

10.6342/NTU.2010.00377

Authors

陳彥鴒

Key Words

胸腺嘧啶激酶1 ; DNA修復 ; 檢查哨 ; 細胞週期 ; TK1 ; DNA Repair ; Checkpoint ; cell cycle

PublicationName

臺灣大學生物化學暨分子生物學研究所學位論文

Volume or Term/Year and Month of Publication

2010年

Academic Degree Category

博士

Advisor

張智芬

Content Language

英文

Chinese Abstract

在DNA複製以及修復時,提供胸苷三磷酸 (dTTP) 用於DNA合成是非常重要的過程。細胞內主要有兩條路徑可以提供dTTP 的合成,分別是新生成和回收路徑。而過去的文獻指出DNA損傷可藉由腫瘤抑制蛋白p53或非p53依賴的訊息傳導,進一步正向調控核苷酸還原酶 (RNR) 所主導的dTTP新生成路徑。此過程可以提供足夠的dTTP供DNA修復使用,而使得細胞有更好的存活率。然而,目前對於dTTP的回收路徑是否亦參與於DNA損傷反應中仍不是非常的清楚。 胸腺嘧啶激酶 (TK)是dTTP回收路徑中的速率決定酵素。由於RNR中的小亞基 (R2) 與細胞質中TK1在細胞週期中受到相似的調控,舉凡在DNA合成時期 (S phase)的轉錄活化以及離開有絲分裂時期的蛋白質降解,因而我提出兩個問題: TK1是否像小亞基 (R2) 會參與DNA 損傷反應,此外腫瘤抑制蛋白p53是否會於DNA損傷時影響dTTP 回收路徑。而在我的研究中發現經過基因毒殺藥劑處理的癌症細胞會誘導TK1表現量上升並且於細胞核中累積。而後也發現p53缺失的細胞於DNA損傷復原的過程中,TK1表現量的累積是導因於細胞透過活化G2檢查哨將其停滯於G2時期,因而缺乏有絲分裂時期的蛋白質降解機制。另外我也發現p53正常的大腸直腸癌細胞在DNA損傷時會透過細胞週期蛋白依賴性激酶抑制劑p21去抑制G1/S時期的進程,導致較少量的細胞停滯於G2時期和較少的TK1累積。因此在DNA發生損傷時,癌症細胞中p53的狀態可透過不同的細胞週期調控而影響TK1誘導的程度。除此之外,我亦發現在p53缺失的大腸直腸癌細胞中,TK1對於細胞的增殖是非必要的但是在DNA損傷復原時dTTP 的補給上卻是重要的。進一步探討於DNA損傷時,經正向調節的TK1主導的dTTP 其功能上的重要性,我證明在DNA損傷復原時抑制TK1表現量會降低DNA修復的效率並導致更多因基因毒性藥劑引起的死亡。總而言之,我的實驗結果暗示在基因毒性藥劑的處裡後,癌症細胞會正向調節TK1而產生較多的dTTP,有助於停滯在G2時期DNA的修復工程。 總結,我的論文研究透過整合DNA 損傷訊息、腫瘤抑制蛋白p53調節路徑、dTTP生成以及TK1的細胞週期調控歸納出負責調節dTTP合成的TK1在化學治療反應中的功能性角色。

English Abstract

Cellular supply of dTTP is essential for DNA synthesis in the DNA replication and repair processes. dTTP biosynthesis is controlled by de novo and salvage pathway. Previous reports have already demonstrated that ribonucleotide reductase (RNR) -mediated de novo pathway for dTTP synthesis is up-regulated by DNA damage signaling in a p53-dependent and p53-independent manner, which contributes to sufficient dTTP supply for DNA repair, thus leading to better survival. However, it is poorly understood whether the regulation of salvage pathway for dTTP synthesis is involved in the DNA damage response. Thymidine kinase (TK) is a rate-limiting enzyme in salvage pathway-mediated dTTP biosyntheis. Since R2 subunits of RNR complex and cytosolic TK1 share similar regulatory modes in terms of S phase-specific transcriptional activation and proteasome-mediated proteolytic control in late mitosis, I raised questions whether TK1, like R2 subunit, participates in DNA damage response and whether p53 affects the salvage pathway-mediated dTTP synthesis following DNA damage. I found that genotoxic insults in tumor cells caused up-regulation and nuclear localization of TK1. Further I discovered that TK1 accumulated in p53-deficient cells during recovery from DNA damage is due to a lack of mitotic proteolysis since these cells are arrested in the G2 phase by checkpoint activation. In addition, I observed that p21 expression in response to DNA damage prohibits G1/S progression, resulting in a smaller G2 fraction and less TK1 accumulation in HCT116 p53-proficient cells. Thus, the p53 status of tumor cells affects the magnitude of TK1 induction after DNA damage through differential cell cycle control. Furthermore, the experimental data were shown that in HCT-116 p53-deficient cells, TK1 is dispensable for cell proliferation, but crucial for dTTP supply during recovery from DNA damage. To further investigate the functional importance of up-regulated TK1-mediated dTTP synthesis in DNA damage response, I found that depletion of TK1 decreases the efficiency of DNA repair during recovery from DNA damage and causes more genotoxic insult-induced lethality. Altogether, experimental data suggest that more dTTP synthesis via TK1 take place after genotoxic insults in tumor cells, improving DNA repair during G2 arrest. In sum, my thesis integrates DNA damage signaling, p53-mediated pathway, dTTP synthesis and cell cycle control of TK1 to define the functional role of TK1 in dTTP regulation in chemotherapeutic response.

Topic Category 醫藥衛生 > 基礎醫學
醫學院 > 生物化學暨分子生物學研究所
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