Department of Chemistry, Center for Integrated Protein Science CIPS, Ludwig-Maximilians University, D-81377 Munich, Germany.
Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20720-5. doi: 10.1073/pnas.1008894107. Epub 2010 Nov 12.
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.
杂环芳香胺在体内产生体积庞大的 C8 鸟嘌呤损伤，干扰和破坏 DNA 和 RNA 的合成。这些损伤因此成为强复制阻断物。此外，大体积加合物会导致点突变和移码突变。跨损伤合成（TLS）DNA 聚合酶 η 能够以无差错的方式绕过缓慢的 C8 体积庞大的加合物损伤，例如广泛研究的 2-氨基芴-dG 及其乙酰化类似物。相反，复制聚合酶完全被乙酰化损伤阻断。在这里，我们表明 TLS 效率 η 取决于形成损伤的体积庞大的加合物的大小。基于晶体结构，我们展示了为什么旁路反应如此困难，并提供了旁路反应的模型。在我们的模型中，TLS 是在不将损伤旋转到反式构象的情况下完成的，这与之前的想法不同。
