人工锌指蛋白随机库的构建及其在锌指核酸酶筛选中的应用研究
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摘要
锌指核酸酶是由能够识别并结合特定DNA序列的人工锌指蛋白和一个非特异性核酸内切酶Fok I融合而成的一种人工合成酶,是目前进行高等生物基因组编辑的一个新工具。锌指蛋白与DNA识别的特异性和结合能力是影响ZFN特异性和效率的最关键要素,所以锌指核酸酶技术的核心是锌指蛋白的构建和筛选。
本研究以zif268型三锌指为基本框架,利用盒式突变方法,将单个锌指α螺旋中?1, +1, +2, +3, +4, +5和+6位置上的7个关键氨基酸的编码序列分别进行随机突变,获得三个人工三锌指蛋白随机库,建立和完善了应用人工锌指蛋白随机库筛选特异性锌指蛋白的技术平台。然后将得到的DYRK1A特异性锌指蛋白与非限制性核酸内切酶FokⅠ连接,构建了DYRK1A锌指核酸酶,应用酵母验证系统测试了DYRK1A锌指核酸酶的特异性和剪切效率。结果如下:
1.建立了三个人工锌指蛋白库(人工锌指1库、人工锌指2库和人工锌指3库)。以人DYRK1A基因为例,测试和验证了该技术平台的可行性和效率。利用网上在线查找工具ZiFit 3.2,确定了人DYRK1A基因的靶位点5'-TCGACCACCAGCATCGGCACA- GTGGTGGGCAG-3',并根据该靶位点设计了一系列报告载体。利用已建立的锌指蛋白库,根据细菌双杂交原理,分别筛选出了结合人DYRK1A基因靶位点中左侧序列和右侧序列的50个三锌指蛋白。
2.本实验建立了锌指核酸酶活性的酵母验证系统。将获得的锌指蛋白与非限制性核酸内切酶Fok I连接,构建成锌指核酸酶表达载体pTrp-ADH1-ZFNL和pLeu-ADH1-ZFNR。根据酵母细胞中断裂双链DNA的修复机制,设计了含有人DYRK1A基因靶序列的报告载体pUra-KanMX4-ZFBS。将该报告载体转入酵母菌JMY31,构建了酵母报告菌株JMY31-DYRK1A。通过对酵母菌落PCR和测序鉴定,含突变KanMX4基因的报告载体在实验组酵母细胞内通过同源重组机制得以修复,修复效率高达90%。测序结果表明,PCR产物为正确的KanMX4基因表达盒,说明突变的KanMX4基因在锌指核酸酶介导下,通过同源重组方式获得准确修复。在酵母细胞内锌指核酸酶活性的验证实验进一步说明了利用细菌双杂交原理,通过开源方式筛选出来的三锌指蛋白对靶位点具有较强的特异性和亲和性。
Zinc-finger nucleases (ZFNs) are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain (Fok I). ZFN can be used to precisely alter the genomes of higher organisms. The creation of designer ZFNs that cleave DNA at a pre-determined site depends on the reliable creation of ZFPs that can specifically recognize the chosen target site within a genome. Therefore, the key step in construction of zinc finger nuclease is the selection of specific zinc finger proteins.
The oligomerized pool engineering (OPEN) approach were applyed to select specific zinc finger proteins in this reseach. Key amino acids at positions ?1, +1, +2, +3, +4, +5 and +6 relative to the start of theα-helix of each zinc finger motif contribute to most of the sequence-specific interactions with the DNA site. Based on three-finger ZFP from a framework Zif2687, the sequences coding seven key amino acids were randomized by Cassette Mutagenesis. Three zinc finger random libraries were constructed subsequently. The ZFPs were fused to the non- specific endonuclease domain of Fok I to form ZFNs. Then the activity of ZFNs was examined in yeast validation system. The results as follows:
1. Three zinc finger random libraries (Randomized zinc finger 1 library, Randomized zinc finger 2 library and Randomized zinc finger 3 library) were constructed. Human DYRK1A gene was exemplified to establish a technology platform for screening of ZFPs. The zinc-finger targeter (ZiFiT) program was used to identify potential full ZFN sites of genomic sequence of human DYRK1A gene. The target sequence is 5'-TCGACCACCAGCATC- GGCACAGTGGTGGGCAG-3'. A serial reporter plasmids were constructed subsequently. Three zinc finger random libraries were used to screen specific zinc finger proteins binding DYRK1A gene. Fifty zinc finger proteins were isolated by bacterial two hybrid.
2. We demonstrated a rapid and precise system to test ZFNs activity in yeast cells. The express plamids pTrp-ADH1-ZFNL和pLeu-ADH1-ZFNR were constructed by by fusing ZFP to a Fok I. In view of repair mechanisms of Double-stranded DNA break in yeast cells, The repoter plasmid pUra-KanMX4-ZFBS were constructed. 90% of the target site in reporter plasmid were cleaved by ZFN, and repaired by mechanism of homologous recombination in yeast JMY31. The results supported the high efficiency of OPEN appoach. Preliminary tests of ZFN activity using the system will simplify experimental operations, improve the success rate of experiments.
本研究以zif268型三锌指为基本框架,利用盒式突变方法,将单个锌指α螺旋中?1, +1, +2, +3, +4, +5和+6位置上的7个关键氨基酸的编码序列分别进行随机突变,获得三个人工三锌指蛋白随机库,建立和完善了应用人工锌指蛋白随机库筛选特异性锌指蛋白的技术平台。然后将得到的DYRK1A特异性锌指蛋白与非限制性核酸内切酶FokⅠ连接,构建了DYRK1A锌指核酸酶,应用酵母验证系统测试了DYRK1A锌指核酸酶的特异性和剪切效率。结果如下:
1.建立了三个人工锌指蛋白库(人工锌指1库、人工锌指2库和人工锌指3库)。以人DYRK1A基因为例,测试和验证了该技术平台的可行性和效率。利用网上在线查找工具ZiFit 3.2,确定了人DYRK1A基因的靶位点5'-TCGACCACCAGCATCGGCACA- GTGGTGGGCAG-3',并根据该靶位点设计了一系列报告载体。利用已建立的锌指蛋白库,根据细菌双杂交原理,分别筛选出了结合人DYRK1A基因靶位点中左侧序列和右侧序列的50个三锌指蛋白。
2.本实验建立了锌指核酸酶活性的酵母验证系统。将获得的锌指蛋白与非限制性核酸内切酶Fok I连接,构建成锌指核酸酶表达载体pTrp-ADH1-ZFNL和pLeu-ADH1-ZFNR。根据酵母细胞中断裂双链DNA的修复机制,设计了含有人DYRK1A基因靶序列的报告载体pUra-KanMX4-ZFBS。将该报告载体转入酵母菌JMY31,构建了酵母报告菌株JMY31-DYRK1A。通过对酵母菌落PCR和测序鉴定,含突变KanMX4基因的报告载体在实验组酵母细胞内通过同源重组机制得以修复,修复效率高达90%。测序结果表明,PCR产物为正确的KanMX4基因表达盒,说明突变的KanMX4基因在锌指核酸酶介导下,通过同源重组方式获得准确修复。在酵母细胞内锌指核酸酶活性的验证实验进一步说明了利用细菌双杂交原理,通过开源方式筛选出来的三锌指蛋白对靶位点具有较强的特异性和亲和性。
Zinc-finger nucleases (ZFNs) are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain (Fok I). ZFN can be used to precisely alter the genomes of higher organisms. The creation of designer ZFNs that cleave DNA at a pre-determined site depends on the reliable creation of ZFPs that can specifically recognize the chosen target site within a genome. Therefore, the key step in construction of zinc finger nuclease is the selection of specific zinc finger proteins.
The oligomerized pool engineering (OPEN) approach were applyed to select specific zinc finger proteins in this reseach. Key amino acids at positions ?1, +1, +2, +3, +4, +5 and +6 relative to the start of theα-helix of each zinc finger motif contribute to most of the sequence-specific interactions with the DNA site. Based on three-finger ZFP from a framework Zif2687, the sequences coding seven key amino acids were randomized by Cassette Mutagenesis. Three zinc finger random libraries were constructed subsequently. The ZFPs were fused to the non- specific endonuclease domain of Fok I to form ZFNs. Then the activity of ZFNs was examined in yeast validation system. The results as follows:
1. Three zinc finger random libraries (Randomized zinc finger 1 library, Randomized zinc finger 2 library and Randomized zinc finger 3 library) were constructed. Human DYRK1A gene was exemplified to establish a technology platform for screening of ZFPs. The zinc-finger targeter (ZiFiT) program was used to identify potential full ZFN sites of genomic sequence of human DYRK1A gene. The target sequence is 5'-TCGACCACCAGCATC- GGCACAGTGGTGGGCAG-3'. A serial reporter plasmids were constructed subsequently. Three zinc finger random libraries were used to screen specific zinc finger proteins binding DYRK1A gene. Fifty zinc finger proteins were isolated by bacterial two hybrid.
2. We demonstrated a rapid and precise system to test ZFNs activity in yeast cells. The express plamids pTrp-ADH1-ZFNL和pLeu-ADH1-ZFNR were constructed by by fusing ZFP to a Fok I. In view of repair mechanisms of Double-stranded DNA break in yeast cells, The repoter plasmid pUra-KanMX4-ZFBS were constructed. 90% of the target site in reporter plasmid were cleaved by ZFN, and repaired by mechanism of homologous recombination in yeast JMY31. The results supported the high efficiency of OPEN appoach. Preliminary tests of ZFN activity using the system will simplify experimental operations, improve the success rate of experiments.
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