Cdc7-Dbf4 透過磷酸化 HSP90 以調節 ATR 依賴型 DNA 複製監控系統

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研究生：	鄭安寧 Cheng, An Ning
論文名稱：	Cdc7-Dbf4 透過磷酸化 HSP90 以調節 ATR 依賴型 DNA 複製監控系統 Cdc7-Dbf4 Phosphorylates HSP90 to Regulate the ATR-mediated S-phase checkpoint
指導教授：	呂平江 Lyu, Ping-Chiang 李岳倫 Lee, Alan Yueh-Luen
口試委員:	謝小燕張茂山王惠君
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	80
中文關鍵詞：	Cdc7-Dbf4 、S-phase Checkpoint 、HSP90 、DNA repair
相關次數：	點閱：2 下載：0
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細胞分裂週期素7 (Cell Division Cycle 7, Cdc7) 是一種絲氨酸-蘇氨酸激酶 (serine-threonine kinase)，與Dbf4結合始有活性。Cdc7-Dbf4激酶不僅是DNA複製起始所需的蛋白，在真核生物複製期檢查點 (S-phase checkpoint) 的訊息傳導也有重要的作用。在哺乳動物中，Cdc7-Dbf4在S期檢查點的功能以及作用機制仍未明。我們先前的研究發現，在DNA受到損傷時，ATM和ATR會磷酸化Dbf4的絲氨酸539的位置，但Cdc7的激酶活性仍然存在未被抑制。因此我們推測在DNA損傷反應（DNA damage response）時，Cdc7-Dbf4可能為ATM和ATR的下游並扮演了調節S期檢查點和抑制DNA複製的角色。前人在酵母菌的研究發現，Cdc7-Dbf4可與熱休克蛋白90 (HSP90) 和HCLK2二者形成的分子伴侶複合體結合一起，而此複合體也可穩定所有包括ATM和ATR之磷脂酰肌醇3-激酶相關激酶（PIKKs）。因此我們推測，HCLK2-HSP90 可能為Cdc7-Dbf4 的下游受質。我們證明了在DNA損傷反應下，CDC7-DBF4與HCLK2-HSP90結合並磷酸化HSP90絲氨酸 164 的位置。利用CDC7激酶的抑製劑PHA-767491，可破壞CDC7-DBF4與HSP90-HCLK2之間的相互作用，並抑制HCLK2-HSP90伴侶功能，證明CDC7激酶的活性對於HCLK2-HSP90之間的相互作用和分子伴侶功能是重要的。此外，抑制HSP90的磷酸化影響ATR激酶、HCLK2和MRE11-Rad50-NBS1 (MRN complex) 複合體的穩定性和功能。綜上所述，CDC7-DBF4藉由磷酸化HSP90來調控S期檢查點以影響的ATR激酶的穩定性，此發現可以解釋CDC7-DBF4在多種癌症中過度表達的現象的原因是促進DNA 修復進而增加癌細胞存活率。未來期望可結合 HSP90 和 CDC7 的抑制劑應用於未來的癌症治療。

Abstract
Cdc7-Dbf4 kinase is not only required for DNA replication but plays important roles in S phase checkpoint signaling in eukaryotes. However, the mechanism underlying Cdc7-Dbf4 functions in the S phase checkpoint in mammals is elusive. Our previous data showed that ATM and ATR phosphorylate Dbf4 in response to DNA damages, but the kinase activity of Cdc7 is still remained. Therefore, we hypothesis that Cdc7-Dbf4 may act as a downstream effector of ATR to regulate the S-phase checkpoints and inhibit DNA replication. HSP90 is upregulated in various cancers and binds with HCLK2 to form a chaperone complex to stabilize all phosphatidylinositol 3-kinase-related kinases (PIKKs) including ATM and ATR. We demonstrated that Cdc7-Dbf4 interacts with HCLK2-HSP90 complex and phosphorylates HSP90 at the N-terminus under DNA damage response. PHA-767491, the inhibitor of Cdc7 kinase, disrupts the interaction of Cdc7-Dbf4 with HSP90-HCLK2 complex and prevents the HCLK2-HSP90 chaperone function, suggesting that the kinase activity of Cdc7 is important for the interaction and function of HCLK2-HSP90 complex. Furthermore, the phosphorylation of HSP90 affects the stability and function of the complex of ATR kinase, HCLK2, and Mre11-Rad50-NBS1. These results suggest that Cdc7-Dbf4 regulates S-phase checkpoint signaling via affecting the stability of ATR kinase through the phosphorylation toward HSP90, providing a rationale why overexpressed Cdc7-Dbf4 promotes cancer cells survival and provides a new insight for cancer therapy.

誌謝    I
摘要    II
Abstract    IV
Abbreviation    XII
Chapter1 Introduction    1
1.1 Cdc7-Dbf4 is a switch of DNA replication initiation    1
1.2 DNA damage response and cell cycle checkpoint    2
1.3 Cdc7-Dbf4 and S-phase checkpoint    3
1.4 HCLK2-HSP90 complex play a role in S-phase checkpoint    5
1.5 The goals of this study    6
Chapter 2 Materials and Methods    8
2.1 Cell culture and Cell synchronization    8
2.2    Antibodies    9
2.3    Whole cell lysate and chromatin isolation    9
2.4    Short hairpin RNA (shRNA) and retroviral infection    10
2.5    In vitro Kinase Assays    11
2.6    Reverse transcription-polymerase chain reaction (RT-PCR)    12
2.7    Immunohistochemistry (IHC) staining    12
2.8    Adenovirus construction and infection    13
2.9    Cell viability and survival assay    13
2.10 Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay    14
2.11 Homologous recombination repair (HR) assay    14
2.12 Single cell gel electrophoresis (Comet Assay)    15
2.13 In-gel digestion    16
2.14 Shotgun proteomic identifications    16
2.15 Fluorescence activated cell sorting (FACS) analysis    18
2.16 Immunofluorescence staining    18
2.17 Statistical methods    19
Chapter 3 Results    21
3.1 Cdc7 kinase overexpression promotes cell survival and protects cells from genotoxic stress-induced apoptosis    21
3.2 Overexpression of Cdc7 slows replication fork progression and promotes DNA repair    22
3.3    Cdc7 overexpression causes DNA damage which is related with excess initiation of DNA replication    24
3.4    Cdc7-Dbf4 interacts with HSP90α-HCLK2    25
3.5    HSP90α is a direct substrate of Cdc7-Dbf4    28
3.6    HSP90-S164A failed to activate the ATR-mediated S-phase checkpoint and HR repair    30
Chapter 4 Discussion    33
4.1 Cdc7 overexpression promotes HR repair to prevent apoptosis in cancer cells    33
4.2 Cdc7 is important for S-phase checkpoint recovery and replication restart    34
4.3 Cdc7 phosphorylates HSP90α S164 to promote HR repair    35
4.4 Inhibition of Cdc7 kinase activity may regulate the chaperone function of HSP90 to provide a new method for cancer therapy    35
Chapter 5 Conclusion    38
Figures    39
Figure 1. Cdc7 overexpression inhibits apoptotic activation in cancer cells in response to genotoxic agents.    39
Figure 2. TUNEL assay of Cdc7 overexpression on genotoxin-induced apoptosis    40
Figure 3. Effect of Cdc7 overexpression on the proliferation rate of DOK cells in response to genotoxic agents.    41
Figure 4. Cdc7 overexpression inhibits apoptotic activation in DOK cells in response to genotoxic agents.    42
Figure 5. Cdc7 overexpression increase H2AX phosphorylation.    43
Figure 6. Cdc7 overexpression causes increase H2AX phosphorylation shown by immunofluorescence.    44
Figure 7. Comet assays indicate DSB formation when Cdc7 is overexpressed.    45
Figure 8. Overexpressed Cdc7 increase H2AX phosphorylation in U2OS cells detected by FACS.    46
Figure 9. Cdc7 overexpression causes replication-mediated DNA double strand break caused by excess replication, which activates the ATR-mediated checkpoint.    47
Figure 10. Cdc7 overexpression inhibits BrdU incorporation.    48
Figure 11. BrdU incorporation is inhibited after Cdc7 transiently overexpression.    49
Figure 12. HCLK2 knock-down cells failed to activate ATR-Chk1 pathway.    50
Figure 13. Cdc7-Dbf4 interacts with HCLK2    51
Figure 14. The association between Cdc7-Dbf4 and HCLK2 increases in response to replication or oxidative stress.    52
Figure 15. Dbf4 interacts with HSP90α.    53
Figure 16. Overexpressed Cdc7 increases HSP90α protein stability.    54
Figure 17. Cdc7 does not influence transcriptional level of HSP90 and HCLK2.    55
Figure 18. Inhibition Cdc7 kinase activity affects the interaction between HSP90 and DNA response proteins.    56
Figure 19. HSP90 inhibitor, 17-AAG causes ATR, HCLK2, TTI1, RAD50 and Chk1 unstable.    57
Figure 20. 17-AAG inhibits the interaction between HSP90α and ATR or Chk1.    58
Figure 21. HSP90α protein and phosphorylation level are increase in response to DNA damage.    59
Figure 22. Cdc7-Dbf4 in vitro kinase assay.    60
Figure 23. Cdc7-Dbf4 phosphorylated Hsp90α on the N- and C- terminus.    61
Figure 24. Cdc7-Dbf4 phosphorylates HIS-HSP90α at serine 164.    62
Figure 25. HSP90α-S164A mutant could not be phosphorylated by Cdc7-Dbf4.    63
Figure 26. HSP90α S164A mutant affects the ATR-CHK1 signaling pathway under DNA damage.    64
Figure 27. HSP90-S164A failed to activate HR repair.    65
Figure 28. The binding affinity between HSP90α-S164A and Chk1 is lower than HSP90α wild-type and Chk1.    66
Figure 29. Scheme of Cdc7-Dbf4 kinase regulate ATR mediate S-phase Checkpoint.    67
Table    68
Table 1. Primers used for HSP90α mutagenesis.    68
Table 2. List of HSP90α phosphorylation sites and peptides identified by mass spectrometry    69
Appendix    70
Appendix 1. Cdc7 overexpression impairs S-phase progression after HU-induced cell arrest.    70
Appendix 2. Cdc7 overexpression stimulates HR repair.    71
Reference    72

                                

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