Structures of mismatch replication errors observed in a DNA polymerase
Structures of mismatch replication errors observed in a DNA polymerase
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DOI：
10.1016/s0092-8674(04)00252-1
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发表时间：
2004-03-19
期刊：
影响因子：
64.5
通讯作者：
Beese, LS
中科院分区：
文献类型：
--
作者：
Johnson, SJ;Beese, LS
准确的DNA复制对于基因组稳定性至关重要。高保真DNA聚合酶维持复制准确性的一种机制涉及到聚合酶在错配碱基对共价掺入时停滞，从而有利于后续的错配切除。一些聚合酶对复制错误保留一种“短期记忆”，能对引物末端多达四个碱基对的错配作出反应。在此，我们对在一种聚合酶活性位点上正在延伸的引物末端所捕获的全部12种可能的错配进行了结构表征。我们的观察结果表明了导致错配诱导聚合酶停滞的四种机制。此外，我们观察了从引物末端延伸多达六个碱基对错配的影响，发现DNA中的长程扭曲将错配的存在传递回酶的活性位点，这提示了复制错误短期记忆的结构基础。
Accurate DNA replication is essential for genomic stability. One mechanism by which high-fidelity DNA polymerases maintain replication accuracy involves stalling of the polymerase in response to covalent incorporation of mismatched base pairs, thereby favoring subsequent mismatch excision. Some polymerases retain a "short-term memory" of replication errors, responding to mismatches up to four base pairs in from the primer terminus. Here we a present a structural characterization of all 12 possible mismatches captured at the growing primer terminus in the active site of a polymerase. Our observations suggest four mechanisms that lead to mismatch-induced stalling of the polymerase. Furthermore, we have observed the effects of extending a mismatch up to six base pairs from the primer terminus and find that long-range distortions in the DNA transmit the presence of the mismatch back to the enzyme active site, suggesting the structural basis for the short-term memory of replication errors.