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The RSF1-ATM-p53 signaling axis in conjunction with ATR or DNA-PK upon DNA damage
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | 이, 영수 | - |
| dc.contributor.author | 김, 기은 | - |
| dc.date.accessioned | 2023-11-16T05:43:54Z | - |
| dc.date.available | 2023-11-16T05:43:54Z | - |
| dc.date.issued | 2023 | - |
| dc.identifier.uri | http://repository.ajou.ac.kr/handle/201003/26834 | - |
| dc.language.iso | en | - |
| dc.title | The RSF1-ATM-p53 signaling axis in conjunction with ATR or DNA-PK upon DNA damage | - |
| dc.title.alternative | DNA 손상에 의해 유도되는 RSF1-ATM-p53 신호전달에서 ATR과 DNA-PK와의 상호관계 규명 | - |
| dc.type | Thesis | - |
| dc.identifier.url | http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000032465 | - |
| dc.subject.keyword | ATM | - |
| dc.subject.keyword | DNA strand break | - |
| dc.subject.keyword | RSF1 | - |
| dc.subject.keyword | DNA damage response | - |
| dc.subject.keyword | p53 | - |
| dc.description.degree | Doctor | - |
| dc.contributor.department | 대학원 의생명과학과 | - |
| dc.contributor.affiliatedAuthor | 김, 기은 | - |
| dc.date.awarded | 2023 | - |
| dc.type.local | Theses | - |
| dc.citation.date | 2023 | - |
| dc.embargo.liftdate | 9999-12-31 | - |
| dc.embargo.terms | 9999-12-31 | - |
| dc.description.tableOfContents | CHAPTER I: Introduction 1
A. DNA damage and genomic instability 2 B. DNA double-strand break repair 2 C. DNA damage response (DDR) 4 D. Ataxia Telangiectasia and related human genetic diseases 6 E. RSF1 and ISWI chromatin remodeling complexes 8 F. Hypothesis and Aims of study 10 CHAPTER II: RSF1 function in response to DNA damage in the nervous system 19 A. Chapter Introduction 20 B. Materials and Methods 23 1. Animals 23 2. Western blot analysis 26 3. Histopathological analysis 27 4. Cloning of mouse/human RSF1 gene and micro-irradiation microscopy 28 5. Image and statistical analyses 29 C. Results 30 1. The Rsf1 conditional knockout animal model is successfully generated for the first time. 30 2. Rsf1 is dispensable for brain development and function. 32 3. Atm or p53 deficiency with Rsf1 inactivation does not affect the brain development and neuronal function. 33 4. Rsf1 is involved in response to exogenously induced DNA damage during neurodevelopment. 36 5. Rsf1 deficiency does not influence DNA break itself induced by drug treatments. 38 6. Rsf1 deficiency prevents expressions of p53 dependent genes involved in apoptosis upon DNA damage. 39 CHAPTER III: The involvement of RSF1 in DNA damage response in collaboration with ATM/ATR/DNA-PK 68 A. Chapter Introduction 69 B. Materials and Methods 73 1. Cell culture 73 2. Generation of Knockout cell-line by CRISPR-Cas9 technique 73 3. Drug treatment for inhibiting ATR or DNA-PK and inducing DNA damage 75 4. Western blot analysis 76 5. Cell proliferation and cell cycle analysis 76 6. MNase assay to estimate chromatin status 78 7. Image and statistical analyses 79 C. Results 80 1. RSF1 knockout, ATM knockout and RSF1/ATM double knockout human cell lines are newly generated. 80 2. All of ATM, ATR and DNA-PK play distinct roles in RSF1 depending on the type of DNA damage. 81 3. RSF1/ATM dKO cells display an intermediate level of cell cycle checkpoint between RSF1 KO and ATM KO cells. 87 4. RSF1 and ATM double deficiency could lead to either relaxation or condensation of chromatin depending on the kind of DNA damage. 89 CHAPTER IV: Discussion and Perspective 108 A. RSF1 is dispensable during brain development, but necessary for the chromatin regulation for p53 dependent apoptotic gene expressions upon DNA damage 109 1. The animal model with Rsf1 deficiency in the nervous system different from Snf2h conditional knockout animal model 109 2. Rsf1 is not involved in spontaneously induced DNA damage during neurogenesis 111 3. Apoptosis defects in RSF1 knockout condition 112 B. PIKKs are differently responded to RSF1 proficiency or deficiency 114 1. Differential regulation of ATM, ATR, and DNA-PK signaling in RSF1 KO condition 114 2. Possible implications of these new findings to the clinical setting 115 CHAPTER V: Reference 122 | - |
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