臺灣博碩士論文加值系統

DNA損傷反應活化細胞週期檢查點（checkpoint）的目的在將細胞週期停止，以利細胞做DNA修復或在無法修復後決定細胞凋亡。過去許多對於活化checkpoint研究，闡明DNA損傷檢查點將細胞週期停止的機制，但是對於checkpoint如何將訊息傳達到修復系統的機制卻不明確。DNA雙股鏈斷（DSB）修復主要以同源性重組（HR）和非同源性末端黏合（NHEJ）兩種方式修復，這兩種修復方式互相合作也互相競爭，共同維護細胞基因體的穩定性。在哺乳類細胞會以NHEJ修復大部分的DSB，但是這種方式修復的結果會有DNA序列變異可能性。所以假設NHEJ並不單純僅是直接做末端黏合，可能有另一種NHEJ路徑存在，這條路徑會使DSB末端以精確的NHEJ修復。ATM與Chk2是DNA DSB損傷反應最重要的checkpoint，最近的研究發現ATM與Chk2依賴性的BRCA1磷酸化會促進細胞以HR的方式做精確性的修復DNA DSB，因此，合理的假設checkpoint蛋白ATM與Chk2也會透過BRCA1降低NHEJ修復的所帶來的錯誤，讓NHEJ修復能夠更加精確而預防基因變異。
本篇論文以細胞內修復線性plasmid DNA為實驗模式測試NHEJ活性，目的是為了探究ATM與Chk2是否調控BRCA1以促進NHEJ修復的精確性。根據實驗觀察，在有BRCA1表現的MCF-7細胞中，降低ATM或Chk2表現會影響NHEJ的活性；在BRCA1缺陷的HCC1937細胞中，恢復表現Chk2無法發揮磷酸化作用的BRCA1變異株並沒有增加NHEJ修復的精確性，相反的，恢復表現正常的BRCA1或模擬Chk2磷酸化作用的BRCA1變異株可以增加NHEJ修復的精確性；而細胞表現不具磷酸激酶活性的Chk2變異株或ATM無法發揮磷酸化作用的Chk2變異株都會負性優勢影響MCF-7細胞NHEJ修復的精確性。這些結果顯示調控HR修復的Checkpoint蛋白ATM和Chk2，會一起調控BRCA1而控制NHEJ以精確性的方式修復。

Homologous recombination (HR) and non-homologous end-joining (NHEJ) are the two mechanisms responsible for repairing DNA double strand breaks (DSBs) and act in either a collaborative or competitive manner in mammalian cells. DSB repaired by NHEJ, may be more complicated than the simple joining of the ends of DSB, since, if nucleotides were lost, it would result in error-prone repair. This has led to the proposal that a subpathway of precise NHEJ exists which can repair DSBs with higher fidelity; this is supported by recent findings that the expression of the HR gene, BRCA1, is causally linked to in vitro and in vivo precise NHEJ activity. To further delineate this mechanism, the present study explored the connection between NHEJ and the cell-cycle checkpoint proteins, ATM and Chk2, known to be involved in activating BRCA1, and tested the hypothesis that ATM and Chk2 promote precise end-joining by BRCA1. Support for this hypothesis came from the observations that (a) knock-down of ATM and Chk2 expression affected end-joining activity; (b) in BRCA1-defective cells, precise end-joining activity was not restored by a BRCA1 mutant lacking the site phosphorylated by Chk2, but was restored by wild-type BRCA1 or a mutant mimicking phosphorylation by Chk2, (c) Chk2 mutants lacking kinase activity or with a mutation at a site phosphorylated by ATM had a dominant negative effect on precise end-joining in BRCA1-expressing cells. These results suggest that the other two HR-regulatory proteins, ATM and Chk2, act jointly to regulate the activity of BRCA1 in controlling the fidelity of DNA end-joining by precise NHEJ.

正文目錄 頁
第一章 緒言…………………………………………………………………………1
第一節 文獻探討………………………………………………………………1
壹、基因變異與癌症…………………………………………………………1
貳、DNA雙股鏈斷損傷反應機制與癌症………………………………………7
參、DNA雙股鏈斷損傷修復機制…………………………………………10
肆、DNA雙股鏈斷損傷反應之訊號傳遞……………………………………18
伍、DNA雙股鏈斷損傷反應與修復系統之訊號傳遞連結…………………23
第二節 研究目的…………………………………………………………………28
第二章 材料與方法…………………………………………………………………29
第一節 細胞培養………………………………………………………………………29
第二節 基因表現質體與點突變……………………………………………………29
第三節 核醣核酸干擾技術與基因轉殖……………………………………………30
第四節 細胞IR損傷敏感性試驗……………………………………………………31
第五節 免疫轉漬分析法………………………………………………………………32
第六節 細胞內DNA末端黏合試驗………………………………………………33
第三章 結果…………………………………………………………………………37
第一節 以siRNA抑制MCF-7細胞之ATM、Chk2和BRCA1表現……………37
第二節 ATM、Chk2和BRCA1影響細胞內NHEJ活性………………………38
第三節 BRCA1促進Precise NHEJ與Chk2的訊息傳遞有關………………40
第四節 ATM磷酸化活化Chk2與促進正確性的NHEJ有關……………………41
第五節 Chk2透過調控BRCA1參與NHEJ………………………………………42
第六節 ATM透過調控BRCA1參與NHEJ…………………………………43
第四章 討論…………………………………………………………………..……55
第一節 研究發現的重要性……………………………………………………55
第二節 HR與NHEJ修復路徑的互動關係…………………………………56
第三節 假說模式………………………………………………………………57
第四節 限制酶處理之DNA斷鏈末端黏合之錯誤修復的可能性…………58
第五節 Chk2參與NHEJ的可能機制…………………………………………60
第六節 ATM參與NHEJ的可能機制……………………………………………63
第七節 討論細胞內修復限制酶處理之DNA末端重新黏合試驗模式……67
第五章 結論………………………………………………………………………70
第六章 參考文獻……………………………………………………………………71

『圖』目錄 頁

圖1 以siRNA抑制MCF-7細胞表現ATM、BRCA1或Chk2…………………………46
圖2 ATM、BRCA1及Chk2的siRNA影響細胞內NHEJ活性……………………47
圖3 PCR-RFLP法試驗ATM、BRCA1及Chk2的siRNA影響細胞內Precise NHEJ活性……………………………………………………………………………………48
圖4 BRCA1參與NHEJ受到PI3-kinase調控…………………………………………49
圖5 BRCA1轉殖於HCC1937細胞可以恢復 NHEJ活性…………………………50
圖6 不同Chk2變異株對MCF-7細胞之NHEJ的優勢效應影響……………………51
圖7 Chk2透過對BRCA1-Ser988磷酸化而促進NHEJ活性……………………52
圖8 降低ATM表現影響BRCA1促進Precise NHEJ…………………………………53
圖9 假說模式………………………………………………………………………54

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