title: Nascent RNA folding mitigates transcription-associated mutagenesis.
abstract: 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.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiaoshu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Yang
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jianzhi
authors.initials: J
authors.lastname: Zhang
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D004271:DNA, Fungal / Q000235:genetics; D030541:Databases, Genetic; D015966:Gene Expression Regulation, Fungal; D055106:Genome-Wide Association Study; D006801:Humans; D016296:Mutagenesis; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D059370:RNA Folding; D016914:Ribonuclease H / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D026923:Amino Acid Transport Systems, Basic; C502212:CAN1 protein, S cerevisiae; D004271:DNA, Fungal; D029701:Saccharomyces cerevisiae Proteins; D016914:Ribonuclease H; C078856:ribonuclease HI