The mismatch repair system promotes DNA polymerase ζ-dependent translesion synthesis in yeast
The mismatch repair system promotes DNA polymerase ζ-dependent translesion synthesis in yeast
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DOI：
10.1073/pnas.0812715106
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发表时间：
2009-04-07
影响因子：
11.1
通讯作者：
Jinks-Robertson, Sue
中科院分区：
文献类型：
--
作者：
Lehner, Kevin;Jinks-Robertson, Sue
阻碍复制的DNA损伤可以通过容易出错或无错误的机制来绕过。容易出错的机制依赖于专门的跨病变合成(TLS)DNA聚合酶，它直接在病变上复制，而无错误的通路使用未受损的双链作为病变旁路的模板。在酿酒酵母中，大多数自发和诱发DNA损伤的诱变TLS依赖于DNA聚合酶Zeta(Pol Zeta)的活性。在这里，我们使用Pol Zeta在移码逆转试验中产生的独特突变特征来检测酵母错配修复(MMR)系统在调节Pol Zeta依赖的突变中的作用。虽然MMR通常通过消除复制DNA聚合酶引入的错误来减少突变，但我们发现MMR系统是Pol Zeta依赖的突变所必需的。然而，在没有同源重组的情况下，容易出错的Pol Zeta途径不受MMR状态的影响。这些结果表明，MMR通过抑制依赖同源重组的替代、无错误的途径来促进Pol Zeta依赖的突变。最后，与其消除复制DNA聚合酶造成的错误的能力相比，我们表明MMR无法有效地纠正Pol Zeta引入的错误。
DNA lesions that block replication can be bypassed by error-prone or error-free mechanisms. Error-prone mechanisms rely on specialized translesion synthesis (TLS) DNA polymerases that directly replicate over the lesion, whereas error-free pathways use an undamaged duplex as a template for lesion bypass. In the yeast Saccharomyces cerevisiae, most mutagenic TLS of spontaneous and induced DNA damage relies on DNA polymerase zeta (Pol zeta) activity. Here, we use a distinct mutational signature produced by Pol zeta in a frameshift-reversion assay to examine the role of the yeast mismatch repair (MMR) system in regulating Pol zeta-dependent mutagenesis. Whereas MMR normally reduces mutagenesis by removing errors introduced by replicative DNA polymerases, we find that the MMR system is required for Pol zeta-dependent mutagenesis. In the absence of homologous recombination, however, the error-prone Pol zeta pathway is not affected by MMR status. These results demonstrate that MMR promotes Pol zeta-dependent mutagenesis by inhibiting an alternative, error-free pathway that depends on homologous recombination. Finally, in contrast to its ability to remove mistakes made by replicative DNA polymerases, we show that MMR fails to efficiently correct errors introduced by Pol zeta.