Translesion DNA synthesis across the heptanone-etheno-2′-deoxycytidine adduct in cells
Translesion DNA synthesis across the heptanone-etheno-2′-deoxycytidine adduct in cells
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DOI：
10.1021/tx0600503
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发表时间：
2006-08-21
影响因子：
4.1
通讯作者：
Moriya, Masaaki
中科院分区：
文献类型：
--
作者：
Pollack, Michael;Yang, In-Young;Moriya, Masaaki
4-氧代-2（E）-壬烯醛是脂质过氧化衍生的产物，与DNA中的dG、dA和dC反应形成庚酮（H）-乙烯基（是的一个元素）加合物。在这三种加合物中，H-是在体外反应中以最大丰度形成的dC的元素，并且已经在结肠直肠癌的C57 BL/6 JAPC（min）小鼠模型中检测到。为了确定该加合物的遗传毒性，合成了位点特异性修饰的寡核苷酸，并将其掺入穿梭载体中。在大肠杆菌和人细胞中复制了修饰的载体。对子代质粒的分析表明，H-是dC的一个元件，它强烈地阻断DNA合成，并在两种宿主中明显地错编码。在细菌中的错误编码频率为40-50%，在三种人类细胞系（着色性干皮病A和变体细胞，以及DNA修复野生型细胞）中超过90%。这两种宿主在编码事件上有很大的不同：在E.在人细胞中dA和dT是优先选择。这些结果表明，这种内源性DNA加合物对这两种生物都具有很强的遗传毒性。
4-Oxo-2(E)-nonenal, a lipid peroxidation-derived product, reacts with dG, dA, and dC in DNA to form heptanone (H)-etheno (is an element of) adducts. Among the three adducts, H-is an element of dC is formed in the greatest abundance in in vitro reactions, and it has been detected in the C57BL/6JAPC(min) mouse model of colorectal cancer. To establish the genotoxic properties of this adduct, a site-specifically modified oligonucleotide was synthesized and incorporated into a shuttle vector. The modified vector was replicated in Escherichia coli and human cells. Analysis of the progeny plasmid has revealed that H-is an element of dC strongly blocks DNA synthesis and markedly miscodes in both hosts. The miscoding frequency was 40-50% in bacteria and more than 90% in three human cell lines (xeroderma pigmentosum A and variant cells, and DNA repair wild-type cells). There was a drastic difference in coding events in these two hosts: dG and dC were almost exclusively inserted opposite the lesion in E. coli, while dA and dT were the preferential choices in human cells. These results indicate that this endogenous DNA adduct is very genotoxic to both organisms.