Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation: A link to tumorigenic activity
Molecular topology of polycyclic aromatic carcinogens determines DNA adduct conformation: A link to tumorigenic activity
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DOI：
10.1006/jmbi.2001.4425
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发表时间：
2001-03-09
影响因子：
5.6
通讯作者：
Patel, DJ
中科院分区：
文献类型：
--
作者：
Lin, CH;Huang, XW;Patel, DJ
我们在下面报告了立体异构的“峡湾”区域反式-反式-苯并[c]菲-N-2-鸟嘌呤（命名为（BPh）G）加合物的溶液结构，该加合物位于（C-（BPh）G-C）（G-C-G）序列背景内的胞嘧啶对面。我们观察到插入的菲环与立体异构体依赖的方向性，而不破坏修改后的（BPh）G.C碱基对。对于1 S立体异构加合物，插入发生在修饰链的5'侧，对于1 R立体异构加合物，插入发生在3'侧，其中S和R-反式异构体通过在苄基环上的所有四个手性碳原子处的镜像平面中的反转而彼此相关。插入的峡湾区域BPH环到螺旋中，而不破坏的修改后的碱基对是通过屈曲的（BPH）GC碱基对，位移的连接键从平面的（BPH）G基地，由BPH苄基环和螺旋桨般的偏差从平面的BPH菲环的椅子皱褶的适应。值得注意的是，对于S和R-反式-反式-BPh-N-2-鸟嘌呤加合物，在没有碱基对破坏的情况下，插入发生在与C相对的小沟侧，这与我们先前证明的对于S和R-反式-反式-BPh-N-6-腺嘌呤加合物，在没有修饰的碱基对破坏的情况下，插入发生在与T相对的大沟侧相反。此外，位于C对面的峡湾区域1 S和1 R-反式-反式（BPh）G加合物的这些结果与早期使用位于胞嘧啶对面的“海湾”区域苯并[a]芘-N-2-鸟嘌呤（指定为（BP）G）加合物的研究形成鲜明对比，其中10 S和10 R-反式-反式立体异构体以相反的方向位于小沟中，而没有修饰的碱基对破坏。它们也与C相反的（BP）G加合物的10 S和10 R-顺式-反式立体异构体形成对比，其中芘环以方向性插入螺旋中，但相对链上的修饰碱基及其配偶体被置换出螺旋。这些结果是特别显着的已知更大的致瘤潜力峡湾地区相比，海湾地区的多环芳烃。致瘤潜力已被链接到修复效率，海湾地区加合物可以很容易地修复，而峡湾地区的对应物是难修复的。我们的结构研究结果提出了DNA加合物构象和修复依赖的诱变活性之间的联系，这可能最终转化为致瘤活性的结构依赖性差异。我们建议，峡湾地区小沟连接的BPh-N-2-鸟嘌呤和大沟连接的BPh-N-6-腺嘌呤加合物是难修复的基础上，我们的观察，菲环intercafates到螺旋没有修改的碱基对中断。因此，螺旋受到的干扰最小，菲环不能被修复机制识别。相比之下，海湾区BP-N-2-G加合物易于修复，因为修复机制可以识别位于小沟中的反式-反式沟对齐立体异构体的芘环，或顺式-反式碱基置换插入立体异构体的破坏的修饰碱基对。(C)北京：科学出版社.
We report below on the solution structures of stereoisomeric "fjord" region trans-anti-benzo[c]phenanthrene-N-2-guanine (designated (BPh)G) adducts positioned opposite cytosine within the (C-(BPh)G-C) (G-C-G) sequence context. We observe intercalation of the phenanthrenyl ring with stereoisomer-dependent directionality, without disruption of the modified (BPh)G.C base-pair. Intercalation occurs to the 5' side of the modified strand for the 1S stereoisomeric adduct and to the 3' side for the 1R stereoisomeric adduct, with the S and R-trans-isomers related to one another by inversion in a mirror plane at all four chiral carbon atoms on the benzylic ring. Intercalation of the fjord region BPh ring into the helix without disruption of the modified base-pair is achieved through buckling of the (BPh)GC base-pair, displacement of the linkage bond from the plane of the (BPh)G base, adaptation of a chair pucker by the BPh benzylic ring and the propeller-like deviation from planarity of the BPh phenanthrenyl ring. It is noteworthy that intercalation without basepair disruption occurs from the minor groove side for S and R-trans-anti BPh-N-2-guanine adducts opposite C, in contrast to our previous demonstration of intercalation without modified base-pair disruption from the major groove side for S and R-trans-anti BPh-N-6-adenine adducts opposite T. Further, these results on fjord region 1S and 1R-trans-anti (BPh)G adducts positioned opposite C are in striking contrast to earlier research with "bay" region benzo[a]pyrene-N-2-guanine (designated (BP)G) adducts positioned opposite cytosine, where 10S and 10R-trans-anti stereoisomers were positioned with opposite directionality in the minor groove without modified base-pair disruption. They also are in contrast to the 10S and 10R-cis-anti stereoisomers of (BP)G adducts opposite C, where the pyrenyl ring is intercalated into the helix with directionality, but the modified base and its partner on the opposite strand are displaced out of the helix. These results are especially significant given the known greater tumorigenic potential of fjord region compared to bay region polycyclic aromatic hydrocarbons. The tumorigenic potential has been linked to repair efficiency such that bay region adducts can be readily repaired while their fjord region counterparts are refractory to repair. Our structural results propose a link between DNA adduct conformation and repair-dependent mutagenic activity, which could ultimately translate into structure-dependent differences in tumorigenic activities. We propose that the fjord region minor groove-linked BPh-N-2-guanine and major groove-linked BPh-N-6-adenine adducts are refractory to repair based on our observations that the phenanthrenyl ring intercafates into the helix without modified base-pair disruption. The helix is therefore minimally perturbed and the phenanthrenyl ring is not available for recognition by the repair machinery. By contrast, the bay region BP-N-2-G adducts are susceptible to repair, since the repair machinery can recognize either the pyrenyl ring positioned in the minor groove for the trans-anti groove-aligned stereoisomers, or the disrupted modified basepair for the cis-anti base-displaced intercalated stereoisomers. (C) 2001 Academic Press.