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研究生：	何彥志 Ho, Yen-Chih
論文名稱：	PARP1招募DNA translocases協同抑制DNA複製的進行並調控DNA受損修復 PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair
指導教授：	廖泓鈞 Liaw, Hung-Jiun
學位類別：	博士 Doctor
系所名稱：	生物科學與科技學院 - 生命科學系 Department of Life Sciences
論文出版年：	2023
畢業學年度：	111
語文別：	英文
論文頁數：	117
中文關鍵詞：	反向複製叉、PARP1 、HLTF 、SHPRH 、ZRANB3 、SMARCAL1
外文關鍵詞：	Fork reversal, PARP1, HLTF, SHPRH, ZRANB3, SMARCAL1
相關次數：	點閱：121 下載：0
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當基因體複製過程遭遇複製壓力產生損傷時，細胞會啟動保護機制促使複製叉停滯並形成反向複製叉的結構，以抑制基因體複製的進行，避免損害持續擴大造成結構瓦解；目前已知PARP1會結合到停滯複製叉抑制DNA複製的進行，然而PARP1並不具helicase功能，有關PARP1抑制DNA複製的調控機制尚待進一步釐清。本篇研究中，我們發現PARP1除了參與調控base/nucleotide excision repair（BER/NER）本身也具有損傷感應蛋白的角色，會和DNA translocases (HLTF、SHPRH、ZRANB3及SMARCAL1)以非依賴PAR活性及DNA的方式形成聚合體，於基因體受損時結合到停滯複製叉，藉由DNA translocases將停滯的複製叉轉換成較穩定的反向複製叉結構，以利DNA複製的重新啟動和DNA修復；由於PAR moiety也具有binding motif的功能，能招募更多蛋白質到停滯的複製叉上，我們認為PARP1/DNA translocase聚合體和與PAR相互作用的蛋白質之間的多價相互作用(multivalent interactions)有助於將PARP1/DNA translocase聚合體招募到停滯的複製叉，這個現象與liquid-liquid phase separation理論相互一致，皆為細胞內蛋白質聚集在特定位點的機制。我們進一步發現在複製壓力下SHPRH也會參與調控抑制基因體複製的進行，表示SHPRH本身即為translocase抑或會協助DNA進行translocation。總結，當細胞遭受複製壓力時，會經由PARP1於偵測到受損後將DNA translocase一同帶到受損複製叉上，促使反向複製叉生成避免損害擴大，並啟動DNA受損修復機制。

Replication fork reversal which restrains DNA replication progression is an important protective mechanism in response to replication stress. PARP1 is recruited to stalled forks to restrain DNA replication. However, PARP1 has no helicase activity, and the mechanism through which PARP1 participates in DNA replication restraint remains unclear. In the present study, we found PARP1 is not only involved in base/nucleotide-excision repair (BER/NER) but also functions as a sensor of replication stress. PARP1 and DNA translocases, including HLTF, SHPRH, ZRANB3, and SMARCAL1 form a complex, and these protein-protein interactions are not mediated through DNA and poly(ADP-ribose) (PAR) activity. In response to replication stress, this complex will bind to the damaged site and promote the formation of reversed fork, and this process depends on PAR activity of PARP1. Since the PAR moiety also functions as binding motif which is able to recruit more proteins to stalled forks, our results suggest that multivalent interactions among PARP1, DNA translocases, and PAR-interacting proteins facilitates the recruitment of PARP1/DNA translocases complexes to stalled forks. Our results are consistent with liquid-liquid phase separation theory which is a widespread mechanism underlying the spatiotemporal protein recruitment process. We further identified the ability of SHPRH to restrain DNA replication upon replication stress, indicating that SHPRH itself could be a DNA translocase or a helper to facilitate DNA translocation. Our results suggest that PARP1 facilitates DNA translocase recruitment to damaged forks, preventing fork collapse and facilitating DNA repair.

中文摘要 I
Abstract II
誌謝     III
Content  IV
Chapter 1. Introduction  1
1.Replication stress, DNA damage response, genomic instability  1
2.Fork reversal  2
3.The function of PARP1  4
4.The function of translocases  7
A.HLTF and SHPRH  7
B.SMARCAL1  9
C.ZRANB3  10
5.Aims of this study  12
Chapter 2. Materials and Methods  13
1.Cell culture  13
2.The generation of gene-knockout T24 cells  13
3.RNA interference  14
4.SIRF assay  14
5.PLA assay  15
6.Western blotting  15
7.Plasmid construction  16
8.Generation of PARP1-GFP and PARP1-K893I-GFP expressing cell lines  17
9.Co-immunoprecipitation (CoIP) assay  17
10.Sister chromatid exchange (SCE)  18
11.EdU click confocal  19
12.Immunofluorescence microscopy  19
13.DNA fiber analysis  20
Chapter 3. PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair  21
1.Results  21
A.PARP1 deletion reduces DNA translocase levels at damaged forks  21
B.PAR activity is crucial for the recruitment of DNA translocases to damaged forks  23
C.PARP1 associates with DNA translocases in vivo  23
D.PARP1 interacts with each DNA translocase through multiple domains  25
E.DNA damage treatment enhances the recruitment of the PARP1/DNA translocase complex to stalled forks  25
F.HLTF and SHPRH facilitate the loading of ZRANB3 to damaged replication forks  26
G.DNA translocases restrain DNA replication upon HU-induced replication stress  26
H.High levels of DNA damage activate intra-S phase checkpoint  27
I.The levels of DNA damage severity affect the outcome of fork progression  28
J.PARP1-KO, HLTF-KO, and SHPRH-depleted cells have high levels of CHK1/CHK2 phosphorylation upon 0.01% MMS treatment  29
K.PARP1- and DNA translocase-depleted cells are defective in DNA repair, resulting in higher levels of DSBs  29
2.Discussion and conclusion  30
3.Figures  37
4.Supplementary Figure  76
5.Tables  77
Chapter 4. Chronic treatment with cisplatin induces chemoresistance through the TIP60-mediated Fanconi anemia and homologous recombination repair pathway  79
1.Abstract  79
2.Results  80
A.Chronic treatment with cisplatin induces the expression of TIP60 to confer chemoresistance  80
B.Depletion of TIP60 sensitizes HONE6 cells to cisplatin  81
C.Depletion of TIP60 results in more frequent stalled forks and elevated DSBs after treatment with cisplatin  82
D.TIP60-deficient HONE6 cells show the decreased frequency of sister chromatid exchange (SCE)  83
E.The expressions of several genes in the HR, FA, and PRR pathways are reduced in HONE6-shTIP60 cells  84
F.TIP60 binds to the promoter of BRCA1 and FANCD2  85
G.Histone H4 is acetylated at the TSS sites of BRCA1 and FANCD2  86
3.Discussion and conclusion  87
4.Figures  91
Reference  104
                                    

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