Human DNA polymerase α has a strong mutagenic potential at the initial steps of DNA synthesis.
Human DNA polymerase α has a strong mutagenic potential at the initial steps of DNA synthesis.
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DOI：
10.1093/nar/gkac1101
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发表时间：
2022-11-28
影响因子：
14.9
通讯作者：
Tahirov, Tahir H.
中科院分区：
文献类型：
--
作者：
Lisova, Alisa E.;Baranovskiy, Andrey G.;Morstadt, Lucia M.;Babayeva, Nigar D.;Tahirov, Tahir H.
DNA聚合酶α（Polα）是DNA复制起始所必需的，对基因组突变有重要贡献。Polα在DNA复制早期阶段的活性和保真度尚未得到很好的研究。在这里，我们表明，在DNA合成的开始，当延伸从引物酶接收的RNA引物时，Polα比在随后的DNA延伸步骤中更具致突变性。动力学和结合研究表明，当Polα与嵌合RNA-DNA引物的核糖核苷酸相互作用时，Polα对模板引物的活性和亲和力显著提高。Polα活性在DNA合成的前六个步骤中变化很大，正确和不正确的dNTP掺入率的偏差导致保真度受损，特别是在RNA引物延伸的第二步。此外，含有RNA-DNA引物的Polα/模板：引物复合物的活性和稳定性增加导致错配延伸的效率更高。
DNA polymerase α (Polα) is essential for DNA replication initiation and makes a notable contribution to genome mutagenesis. The activity and fidelity of Polα during the early steps of DNA replication have not been well studied. Here we show that at the beginning of DNA synthesis, when extending the RNA primer received from primase, Polα is more mutagenic than during the later DNA elongation steps. Kinetic and binding studies revealed substantially higher activity and affinity to the template:primer when Polα interacts with ribonucleotides of a chimeric RNA–DNA primer. Polα activity greatly varies during first six steps of DNA synthesis, and the bias in the rates of correct and incorrect dNTP incorporation leads to impaired fidelity, especially upon the second step of RNA primer extension. Furthermore, increased activity and stability of Polα/template:primer complexes containing RNA–DNA primers result in higher efficiency of mismatch extension.
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