Chen Xiaoshu, Yang Jian-Rong, Zhang Jianzhi
Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Genome Res. 2016 Jan;26(1):50-9. doi: 10.1101/gr.195164.115. Epub 2015 Oct 30.
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.
转录具有致突变性，部分原因是新生RNA与其DNA模板结合形成的R环会使非模板DNA链暴露于诱变剂中，并引发非预定的易出错DNA合成。我们假设新生RNA的强烈折叠会削弱R环，从而降低诱变率。通过酵母正向突变试验，我们表明通过报告基因中的同义变化增强RNA折叠并减少R环形成可使突变率降低80%以上。在编码核糖核酸酶H1的基因过表达后，这种效应会减弱，该酶会降解DNA-RNA杂交体中的RNA，这表明该效应依赖于R环。对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尤为重要，因为它们频繁转录且RNA折叠强烈，后者还能提高翻译保真度。因此，增强RNA折叠同时减少基因型和表型突变。
