Effect of mismatch repair on the mutational footprint of the bacterial SOS mutator activity.

Effect of mismatch repair on the mutational footprint of the bacterial SOS mutator activity.
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DOI:
10.1016/j.dnarep.2021.103130
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发表时间:
2021-07
期刊:
影响因子:
3.8
通讯作者:
Culyba MJ
Culyba MJ
中科院分区:
医学3区
文献类型:
--
作者:
Lewis EB;Mudipalli R;Eghbal MM;Culyba MJ

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细菌对DNA损伤的SOS反应诱导了一种容易出错的修复程序,该程序具有突变性。在大肠杆菌中,SOS诱导的突变是由两个容易出错的聚合酶(EPPS)的跨病变合成(TLS)活性引起的,即POL IV和POL V。EPPS的突变足迹受到DNA损伤和修复的混淆,因为突变通过TLS靶向DNA损伤,并被错配修复(MMR)系统纠正。为了去除这些因素并在全基因组范围内评估非靶向EPP突变,我们构建了MMR缺失的自发SOS突变株,然后通过突变积累和全基因组测序分析了它们的突变足迹。我们的分析揭示了非靶向SOS突变的新特征,显示了MMR如何改变其光谱、序列特异性和链偏见。我们的数据支持这样一种模型,即EPP倾向于作用于复制叉子的滞后链,产生碱基对错配,并由MMR根据错配的类型进行差异化修复。
The bacterial SOS response to DNA damage induces an error-prone repair program that is mutagenic. In Escherichia coli, SOS-induced mutations are caused by the translesion synthesis (TLS) activity of two error-prone polymerases (EPPs), Pol IV and Pol V. The mutational footprint of the EPPs is confounded by both DNA damage and repair, as mutations are targeted to DNA lesions via TLS and corrected by the mismatch repair (MMR) system. To remove these factors and assess untargeted EPP mutations genome-wide, we constructed spontaneous SOS mutator strains deficient in MMR, then analyzed their mutational footprints by mutation accumulation and whole genome sequencing. Our analysis reveals new features of untargeted SOS-mutagenesis, showing how MMR alters its spectrum, sequence specificity, and strand-bias. Our data support a model where the EPPs prefer to act on the lagging strand of the replication fork, producing base pair mismatches that are differentially repaired by MMR depending on the type of mismatch.
DOI: 10.1007/bf00339621
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