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系統識別號 U0026-3006201112143100
論文名稱(中文) ZBRK1在DNA損傷反應中的基因調控與功能探討
論文名稱(英文) Characterization of ZBRK1 gene regulation and function in DNA damage response
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 廖靖君
研究生(英文) Ching-Chun Liao
學號 s5895101
學位類別 博士
語文別 英文
論文頁數 92頁
口試委員 指導教授-王育民
指導教授-張文昌
召集委員-呂增宏
口試委員-沈孟儒
口試委員-洪文俊
口試委員-楊性芳
中文關鍵字 基因調控 
英文關鍵字 DNA damage  RB  ZBRK1  E2F1 
學科別分類
中文摘要 視網膜母细胞瘤蛋白(retinoblastoma protein, RB)除了具有重要的腫瘤抑制功能,也被認為在DNA損傷所導致的細胞週期停滯中扮演重要的角色,且可調控許多與DNA修復相關的因子。然而在DNA損傷反應中,RB如何藉由轉錄機制調控與生長停滯相關的基因仍不是非常清楚。我們探討在DNA損傷反應中,RB是否可以藉由調控ZBRK1這個可以調控DNA損傷反應中重要基因GADD45A的鋅手指的轉錄因子,進而導致細胞週期的停滯。實驗結果發現ZBRK1基因啟動區包含一個會專一與E2F1結合,但不會與E2F4和E2F6結合的E2F結合序列,同時更發現RB, CtIP, CtBP與E2F1會形成複合體,在UV及MMS刺激下共同抑制ZBRK1基因轉錄。除此之外,我們證明了即使ZBRK1的結合蛋白BRCA1及KAP1在DNA損傷時會累積在DNA損傷位置,ZBRK1本身並不會出現在DNA損傷位置。表示ZBRK1主要透過調控下游基因的轉錄調控而參與在DNA損傷的反應中。進一步研究結果中也發現,缺乏ZBRK1表現的會導致 GADD45A及ANG1表現量增加,且使細胞受到UV及MMS刺激時不會產生大量的DNA損傷累積。綜上所述,我們的研究結果證明RB/E2F1複合體在抑制ZBRK1轉錄機制上扮演重要角色,並且當此抑制功能失去時,會使得DNA損傷累積導致血管新生以及癌症的形成。
英文摘要 Despite the critical importance of retinoblastoma protein (RB) function in tumor suppression, RB also has an essential role in DNA damage-induced growth arrest and regulates the expression of several factors essential for DNA repair machinery. However, how RB coordinates DNA damage response through transcriptional regulation of genes involved in growth arrest remains largely unexplored. We examined whether RB can mediate the response to DNA damage through modulation of ZBRK1, a zinc finger-containing transcriptional repressor that can modulate the expression of GADD45A, a DNA damage response gene, to induce cell cycle arrest in response to DNA damage. We found that ZBRK1 promoter contains an authentic E2F-recognition sequence that specifically binds E2F1, but not E2F4 or E2F6. Moreover, through this E2F motif, E2F1 can interact with RB, CtIP, and CtBP to form a complex for repressing ZBRK1 gene transcription upon UV and MMS treatment. Alternatively, we demonstrated that ZBRK1 does not localize to the DNA damage foci, even its interaction proteins BRCA1 and KAP1 have been shown to bind these foci. This suggests that ZBRK1-mediated DNA damage response may majorly through a transcription-dependent manner. Furthermore, loss of ZBRK1 expression in cells can result in GADD45A and ANG1 gene activation and shows a resistant effect in UV- and MMS-induced DNA damage. Taken together, these results suggest that the RB/E2F1 complex plays a critical role in ZBRK1 transcriptional repression and loss of this repression may contribute to the sensitivity of DNA damage insults intimately linked to angiogenesis and carcinogenesis.
論文目次 Abstract i
中文摘要 ii
致謝 iii
Contents iv
Abbreviation List ix

Chapter 1 Introduction

1.1 The DNA damage response 1
1.1.2 The DNA damage inducers 1
1.1.3 The DNA repair mechanism 2
1.2 Zinc finger protein (ZFP) 3
1.2.1 Krüpple-associated box-containing zinc-finger proteins (KRAB–ZFPs) 4
1.2.2 Zinc finger and BRCA1-interacting protein with a KRAB domain-1 (ZBRK1) 4
1.2.3 The role of ZBRK1 in DNA damage response 5
1.3 The RB/E2F pathway 6
1.3.1 Retinoblastoma protein (RB) 7
1.3.2 E2F-family proteins 8
1.3.3 The role of RB in DNA damage response 9
1.4 The DNA damage and angiogenesis 10
1.4.2 The role of ZBRK1 in angiogenesis 10
1.5 Specific aims 11


Chapter 2 Materials and methods

2.1 Materials 12
2.2 Methods 12
Cell Culture and Treatment of DNA Damage Agents 12
Plasmid Construction 13
Transfection and Reporter Gene Assay 13
Reverse Transcription Polymerase Chain Reaction (RT-PCR) 14
Western Blot and DNA Affinity Precipitation Assay (DAPA) 14
Chromatin immunoprecipitation (ChIP) and re-ChIP Assay 15
Comet Assay 16
Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) Assay 16
Lentiviral shRNA 17
Microscopy and UVA-laser Irradiation 17


Chapter 3 Results

RB protein level is inversely associated with ZBRK1 transcript level. 18
The E2F recognition site identified on the ZBRK1 promoter is biologically active. 18
E2F1, but not E2F4 or E2F6, acts as a negative regulator of the ZBRK1 promoter. 19
RB is crucial for E2F1-mediated repression of ZBRK1 reporter activity. 20
RB acts as a negative regulator of the ZBRK1 promoter through the E2F motif. 20
Interaction of CtIP with CtBP is important for RB/E2F1-mediated repression of ZBRK1 reporter activity. 21
E2F1/Rb/CtIP/CtBP complex binds to the E2F motif of ZBRK1 promoter. 21
Loss of RB can induce ZBRK1 expression and results in an increase in the DNA damage response. 22
Half-life of endogenous ZBRK1 is shorter than that of exogenous GFP-ZBRK1. 23
E2F1/RB/CtIP/CtBP-mediated ZBRK1 repression is involved in both UV- and MMS-induced DNA damage response. 23
ZBRK1 does not localize to the DNA damage foci. 24
Depletion of ZBRK1 results in an increase in GADD45A expression. 24
Depletion of ZBRK1 protects cells from UV- and MMS-induced DNA damage. 25
Loss of ZBRK1 upon DNA damage response is associated with angiogenesis related genes. 25
ZBRK1 and KAP1 lose the repressive effect on ANG1 transcription after UV treatment. 26


Chapter 4 Discussion 28
References 36
Figures 43
Appendixes 65
Curriculum Vitae 68
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