Nascent RNA folding mitigates transcription-associated mutagenesis.
Nascent RNA folding mitigates transcription-associated mutagenesis.
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DOI：
10.1101/gr.195164.115
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发表时间：
2016-01
期刊：
影响因子：
7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Chen X;Yang JR;Zhang J
转录是诱变的，部分原因是新生RNA与其DNA模板结合形成的r环将非模板DNA链暴露于诱变剂中，并启动了计划外的容易出错的DNA合成。我们假设新生RNA的强折叠削弱了r -环，从而减少了诱变。通过酵母正向突变实验，我们发现通过报告基因的同义改变来加强RNA折叠和减少r环的形成可以降低80%的突变率。这种作用在编码RNA酶H1的基因过表达后减弱，该基因在DNA-RNA杂交中降解RNA，表明这种作用依赖于r环。酵母突变积累系和人类中性多态性的基因组数据分析证实了这些发现的普遍性。这种局部保护基因组完整性的机制对高表达基因特别重要，因为它们的转录频繁，RNA折叠强，后者也提高了翻译保真度。因此，加强RNA折叠同时减少基因型和表型突变。
Transcription is mutagenic, in part because the R-loop formed by the binding of the nascent RNA with its DNA template exposes the nontemplate DNA strand to mutagens and primes unscheduled error-prone DNA synthesis. We hypothesize that strong folding of nascent RNA weakens R-loops and hence decreases mutagenesis. By a yeast forward mutation assay, we show that strengthening RNA folding and reducing R-loop formation by synonymous changes in a reporter gene can lower mutation rate by >80%. This effect is diminished after the overexpression of the gene encoding RNase H1 that degrades the RNA in a DNA–RNA hybrid, indicating that the effect is R-loop-dependent. Analysis of genomic data of yeast mutation accumulation lines and human neutral polymorphisms confirms the generality of these findings. This mechanism for local protection of genome integrity is of special importance to highly expressed genes because of their frequent transcription and strong RNA folding, the latter also improves translational fidelity. As a result, strengthening RNA folding simultaneously curtails genotypic and phenotypic mutations.