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首页> 外文期刊>PLoS Genetics >Persistent damaged bases in DNA allow mutagenic break repair in Escherichia coli
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Persistent damaged bases in DNA allow mutagenic break repair in Escherichia coli

机译：DNA中持久受损的碱基可在大肠杆菌中诱变断裂修复

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Bacteria, yeast and human cancer cells possess mechanisms of mutagenesis upregulated by stress responses. Stress-inducible mutagenesis potentially accelerates adaptation, and may provide important models for mutagenesis that drives cancers, host pathogen interactions, antibiotic resistance and possibly much of evolution generally. In Escherichia coli repair of double-strand breaks (DSBs) becomes mutagenic, using low-fidelity DNA polymerases under the control of the SOS DNA-damage response and RpoS general stress response, which upregulate and allow the action of error-prone DNA polymerases IV (DinB), II and V to make mutations during repair. Pol IV is implied to compete with and replace high-fidelity DNA polymerases at the DSB-repair replisome, causing mutagenesis. We report that up-regulated Pol IV is not sufficient for mutagenic break repair (MBR); damaged bases in the DNA are also required, and that in starvation-stressed cells, these are caused by reactive-oxygen species (ROS). First, MBR is reduced by either ROS-scavenging agents or constitutive activation of oxidative-damage responses, both of which reduce cellular ROS levels. The ROS promote MBR other than by causing DSBs, saturating mismatch repair, oxidizing proteins, or inducing the SOS response or the general stress response. We find that ROS drive MBR through oxidized guanines (8-oxo-dG) in DNA, in that overproduction of a glycosylase that removes 8-oxo-dG from DNA prevents MBR. Further, other damaged DNA bases can substitute for 8-oxo-dG because ROS-scavenged cells resume MBR if either DNA pyrimidine dimers or alkylated bases are induced. We hypothesize that damaged bases in DNA pause the replisome and allow the critical switch from high fidelity to error-prone DNA polymerases in the DSB-repair replisome, thus allowing MBR. The data imply that in addition to the indirect stress-response controlled switch to MBR, a direct cis-acting switch to MBR occurs independently of DNA breakage, caused by ROS oxidation of DNA potentially regulated by ROS regulators.
机译：细菌，酵母和人类癌细胞具有通过应激反应上调的诱变机制。应激诱导诱变可能会加速适应，并可能为诱变提供重要的模型，从而诱使癌症，宿主病原体相互作用，抗生素耐药性以及可能普遍产生许多进化。在大肠杆菌中，使用低保真DNA聚合酶在SOS DNA损伤反应和RpoS一般应激反应的控制下，双链断裂（DSB）的修复变得诱变，从而上调并允许容易出错的DNA聚合酶IV （DinB），II和V在修复过程中发生突变。 Pol IV暗示与DSB修复复制体竞争并取代高保真DNA聚合酶，从而引起诱变。我们报告说，上调的Pol IV不足以进行诱变断裂修复（MBR）;还需要DNA中受损的碱基，而在饥饿中的细胞中，这些碱基是由活性氧（ROS）引起的。首先，MBR通过ROS清除剂或氧化损伤反应的组成性激活而降低，这两者都降低了细胞ROS水平。 ROS除了引起DSB，饱和错配修复，氧化蛋白质或诱导SOS反应或一般应激反应外，还促进MBR。我们发现ROS通过DNA中的氧化鸟嘌呤（8-oxo-dG）驱动MBR，因为从DNA去除8-oxo-dG的糖基化酶的过量生产会阻止MBR。此外，其他受损的DNA碱基可以替代8-oxo-dG，因为如果诱导了DNA嘧啶二聚体或烷基化碱基，ROS清除的细胞将恢复MBR。我们假设DNA中受损的碱基使复制体暂停，并允许从高保真到DSB修复复制体中容易出错的DNA聚合酶的关键转换，从而允许MBR。数据表明，除了间接的应力响应控制的向MBR的转换之外，直接向顺式作用的向MBR的转换独立于DNA断裂而发生，这是由可能由ROS调节剂调节的DNA的ROS氧化引起的。

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