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首页> 外文期刊>PLoS Biology >Def1 Promotes the Degradation of Pol3 for Polymerase Exchange to Occur During DNA-Damage–Induced Mutagenesis in Saccharomyces cerevisiae
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Def1 Promotes the Degradation of Pol3 for Polymerase Exchange to Occur During DNA-Damage–Induced Mutagenesis in Saccharomyces cerevisiae

机译：Def1促进Pol3的降解，在酿酒酵母中DNA损伤诱导的诱变过程中发生聚合酶交换。

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摘要

DNA damages hinder the advance of replication forks because of the inability of the replicative polymerases to synthesize across most DNA lesions. Because stalled replication forks are prone to undergo DNA breakage and recombination that can lead to chromosomal rearrangements and cell death, cells possess different mechanisms to ensure the continuity of replication on damaged templates. Specialized, translesion synthesis (TLS) polymerases can take over synthesis at DNA damage sites. TLS polymerases synthesize DNA with a high error rate and are responsible for damage-induced mutagenesis, so their activity must be strictly regulated. However, the mechanism that allows their replacement of the replicative polymerase is unknown. Here, using protein complex purification and yeast genetic tools, we identify Def1 as a key factor for damage-induced mutagenesis in yeast. In in vivo experiments we demonstrate that upon DNA damage, Def1 promotes the ubiquitylation and subsequent proteasomal degradation of Pol3, the catalytic subunit of the replicative polymerase δ, whereas Pol31 and Pol32, the other two subunits of polymerase δ, are not affected. We also show that purified Pol31 and Pol32 can form a complex with the TLS polymerase Rev1. Our results imply that TLS polymerases carry out DNA lesion bypass only after the Def1-assisted removal of Pol3 from the stalled replication fork.
机译：DNA损伤阻碍了复制叉的发展，因为复制型聚合酶无法在大多数DNA损伤中合成。由于停滞的复制叉易于发生DNA断裂和重组，从而导致染色体重排和细胞死亡，因此细胞具有不同的机制来确保在受损模板上复制的连续性。专门的跨病变合成（TLS）聚合酶可以取代DNA损伤部位的合成。 TLS聚合酶以较高的错误率合成DNA，并导致损伤诱导的诱变，因此必须严格调节其活性。但是，使它们替换复制性聚合酶的机制尚不清楚。在这里，使用蛋白质复合物纯化和酵母遗传工具，我们确定Def1为酵母中损伤诱导的诱变的关键因素。在体内实验中，我们证明了DNA受损后，Def1会促进泛型化和随后的蛋白酶体降解，即复制聚合酶δ的催化亚基Pol3，而聚合酶δ的其他两个亚基Pol31和Pol32则不受影响。我们还显示纯化的Pol31和Pol32可以与TLS聚合酶Rev1形成复合物。我们的结果表明，只有在Def1协助从停滞的复制叉中去除Pol3之后，TLS聚合酶才进行DNA损伤旁路。

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