Mechanism of replication blocking and bypass of Y-family polymerase η by bulky acetylaminofluorene DNA adducts
Mechanism of replication blocking and bypass of Y-family polymerase η by bulky acetylaminofluorene DNA adducts
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DOI：
10.1073/pnas.1008894107
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发表时间：
2010-11
期刊：
影响因子：
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通讯作者：
S. Schorr;S. Schneider;K. Lammens;K. Hopfner;T. Carell
中科院分区：
文献类型：
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作者：
S. Schorr;S. Schneider;K. Lammens;K. Hopfner;T. Carell
杂环芳香胺在体内产生大量C8鸟嘌呤病变，干扰和破坏DNA和RNA的合成。因此，这些病变是很强的复制障碍。此外，庞大的加合物会引起点突变和移码突变。翻译合成（TLS） DNA聚合酶η能够以无差错的方式绕过缓慢的C8大体积加合物损伤，如广泛研究的2-氨基芴- dg及其乙酰化类似物。相反，复制聚合酶被乙酰化病变完全阻断。在这里，我们发现Pol η的TLS效率主要取决于形成病变的大块加合物的大小。从晶体结构的角度分析了旁路反应困难的原因，并给出了旁路反应的模型。在我们的模型中，TLS是在没有像之前认为的那样将病变旋转成反构象的情况下完成的。
Heterocyclic aromatic amines produce bulky C8 guanine lesions in vivo, which interfere and disrupt DNA and RNA synthesis. These lesions are consequently strong replication blocks. In addition bulky adducts give rise to point and frameshift mutations. The translesion synthesis (TLS) DNA polymerase η is able to bypass slowly C8 bulky adduct lesions such as the widely studied 2-aminofluorene-dG and its acetylated analogue mainly in an error-free manner. Replicative polymerases are in contrast fully blocked by the acetylated lesion. Here, we show that TLS efficiency of Pol η depends critically on the size of the bulky adduct forming the lesion. Based on the crystal structure, we show why the bypass reaction is so difficult and we provide a model for the bypass reaction. In our model, TLS is accomplished without rotation of the lesion into the anti conformation as previously thought.