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首页> 外文期刊>Biochemistry >Stereospecific differences in repair by human cell extracts of synthesized oligonucleotides containing trans-opened 7,8,9, 10-tetrahydrobenzo(a)pyrene 7,8-diol 9,10-epoxide N2-dG adduct stereoisomers located within the human K-ras codon 12 sequence.
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Stereospecific differences in repair by human cell extracts of synthesized oligonucleotides containing trans-opened 7,8,9, 10-tetrahydrobenzo(a)pyrene 7,8-diol 9,10-epoxide N2-dG adduct stereoisomers located within the human K-ras codon 12 sequence.

机译：人细胞提取物修复的合成寡核苷酸中的立体特异性差异，该寡核苷酸包含位于人K-ras内的反式打开的7,8,9,10-四氢苯并（a）py 7,8-二醇9,10-环氧N2-dG加合物立体异构体密码子12序列。

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摘要

The potent environmental carcinogen benzo[a]pyrene (BaP), following enzymatic activation to enantiomeric pairs of bay-region 7,8-diol 9, 10-epoxides (the benzylic 7-hydroxyl group and epoxide oxygen are cis for DE-1 diastereomers and trans for DE-2 diastereomers), reacts with DNA to form covalent adducts predominately at the exocyclic amino groups of purines. Specific adducts, corresponding to the trans opening of each of the four optically active BaP DE isomers at C-10 by the N 2-amino group of dG, were synthesized as appropriately blocked phosphoramidites and were incorporated at either the first or second G of codon 12 within the G-rich sequence of human K-ras codons 11-13: GCT G1G2T GGC. The adducted oligonucleotides were incorporated into plasmids by primer extension, followed by purification of the covalently closed circular constructs. Adducts derived from either (+)- or (-)-DE-2, placed at either G1 or G2, presented strong blocks to in vitro transcription elongation by bacteriophage T3 RNA polymerase, but only moderately blocked transcription elongation by human RNA polymerase II in nuclear extracts. Adducts derived from all four DEs, placed on either G1 or G2, were used as substrates in a DNA repair synthesis assay using human whole cell extracts. Adducts derived from three of the DE stereoisomers exhibited significant amounts of repair synthesis, but the (-)-DE-2 adduct experienced no repair synthesis above that of the control. Constructs containing a pre-existing nick at the sixth phosphodiester bond 3' to either (+)-DE-2 or (-)-DE-2 adducts exhibited increased repair synthesis.
机译：强大的环境致癌物苯并[a] re（BaP），经酶促活化形成海湾区7,8-二醇9、10-环氧化物的对映体对（苄基7-羟基和环氧化物氧是DE-1非对映异构体的顺式（对于DE-2非对映异构体而言，则是反式），与DNA反应，主要在嘌呤的环外氨基上形成共价加合物。合成了相应的特定加合物，该加合物对应于四种光学活性BaP DE异构体在d-10上的dG的N 2-氨基在C-10上的反式打开，并作为适当封端的亚磷酰胺合成，并掺入了第一个或第二个G密码子人类K-ras密码子11-13的富含G的序列中的12：GCT G1G2T GGC。通过引物延伸将加成的寡核苷酸掺入质粒，随后纯化共价封闭的环状构建体。源自（+）-或（-）-DE-2的加合物位于G1或G2上，对噬菌体T3 RNA聚合酶的体外转录延伸表现出强力阻滞作用，但在一定程度上只能阻止人RNA聚合酶II的转录延伸作用。核提取物。在使用人全细胞提取物的DNA修复合成测定中，将来自所有四个DE的加合物置于G1或G2上用作底物。衍生自三种DE立体异构体的加合物显示出大量的修复合成，但（-）-DE-2加合物未发生高于对照的修复合成。在（+）-DE-2或（-）-DE-2加合物的第六个磷酸二酯键3'处包含预先存在的缺口的构建体，其修复合成增加。

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