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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of DNA polymerase β with a benzo[c]phenanthrene diol epoxide-adducted template exhibits mutagenic features
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Structure of DNA polymerase β with a benzo[c]phenanthrene diol epoxide-adducted template exhibits mutagenic features

机译：带有苯并[c]菲二醇环氧化物加成模板的DNA聚合酶β的结构表现出诱变特性

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摘要

We have determined the crystal structure of the human base excision repair enzyme DNA polymerase β (Pol β) in complex with a 1-nt gapped DNA substrate containing a template N~2-guanine adduct of the tumorigenic (-)-benzo[c]phenanthrene 4R,3S-diol 2S,1R-epoxide in the gap. Nucleotide insertion opposite this adduct favors incorrect purine nucleotides over the correct dCMP and hence can be mutagenic. The structure reveals that the phenan-threne ring system is stacked with the base pair immediately 3' to the modified guanine, thereby occluding the normal binding site for the correct incoming nucleoside triphosphate. The modified guanine base is displaced downstream and prevents the polymerase from achieving the catalytically competent closed conformation. The incoming nucleotide binding pocket is distorted, and the adducted deoxyguanosine is in a syn conformation, exposing its Hoogsteen edge, which can hydrogen-bond with dATP or dGTP. In a reconstituted base excision repair system, repair of a deaminated cytosine (i.e., uracil) opposite the adducted guanine was dramatically decreased at the Pol β insertion step, but not blocked. The efficiency of gap-filling dCMP insertion opposite the adduct was diminished by > 6 orders of magnitude compared with an unad-ducted templating guanine. In contrast, significant misinsertion of purine nucleotides (but not dTMP) opposite the adducted guanine was observed. Pol β also misinserts a purine nucleotide opposite the adduct with ungapped DNA and exhibits limited bypass DNA synthesis. These results indicate that Pol β-dependent base excision repair of uracil opposite, or replication through, this bulky DNA adduct can be mutagenic.
机译：我们已经确定了人类碱基切除修复酶DNA聚合酶β（Polβ）的晶体结构，该结构与包含致瘤性（-）-苯并[N]的模板N〜2-鸟嘌呤加合物的1-nt缺口DNA底物形成复合物。缝隙中有菲4R，3S-二醇2S，1R-环氧。与该加合物相反的核苷酸插入会比正确的dCMP更支持不正确的嘌呤核苷酸，因此可能是诱变的。该结构表明，菲-蒽环系统的碱基对与修饰的鸟嘌呤紧靠3'堆叠，从而遮蔽了正确的传入核苷三磷酸的正常结合位点。修饰的鸟嘌呤碱基向下游移位并阻止聚合酶获得催化有效的闭合构象。传入的核苷酸结合袋变形，加成的脱氧鸟苷呈顺式构象，暴露出其Hoogsteen边缘，该边缘可与dATP或dGTP氢键结合。在重构的基础切除修复系统中，在Polβ插入步骤中，与加成的鸟嘌呤相对的脱氨基胞嘧啶（即尿嘧啶）的修复显着减少，但没有被阻止。与未加成模板的鸟嘌呤相比，与加成图相反的间隙填充dCMP插入的效率降低了> 6个数量级。相反，观察到与加成的鸟嘌呤相反的嘌呤核苷酸（而不是dTMP）有明显的错误插入。 Polβ还与未加盖的DNA误插入了与加合物相对的嘌呤核苷酸，并显示出有限的旁路DNA合成。这些结果表明，与这种庞大的DNA加合物相反或通过其复制的尿嘧啶的Polβ依赖性碱基切除修复可能是诱变的。

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