Nascent RNA folding mitigates transcription-associated mutagenesis

Chen, Xiaoshu; Yang, Jian; Zhang, Jianzhi

doi:10.1101/gr.195164.115

Cited by 19 publications

(34 citation statements)

References 58 publications

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“…4A). We kept features that may influence local mutation rate such as GC content, codon usage, and predicted local mRNA structure largely unchanged (Table S4) [13,17,25]. The expression levels of URA3 in these variants are also identical ( Fig.…”

Section: Genetic Manipulation Of Dna Curvature Affects Mutation Ratementioning

confidence: 99%

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DNA local structure decreases mutation rates

Duan

Huan

Chen³

et al. 2018

Preprint

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Running title: Intrinsic DNA curvature decreases local mutation rates 2 ABSTRACT Background Mutation rates vary across the genome. Whereas many trans factors that influence mutation rates have been identified, as have specific sequence motifs at the 1-7 bp scale, cis elements remain poorly characterized. The lack of understanding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis. ResultsHere we show, using a combination of synthetic genes and sequencing of thousands of isolated yeast colonies, that intrinsic DNA curvature is the major cis determinant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast cells and human tumors accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity, and not due to differences in the local activity of DNA repair. ConclusionsOur study establishes a framework in understanding the cis properties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.

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Section: Genetic Manipulation Of Dna Curvature Affects Mutation Ratementioning

confidence: 99%

“…A large number of trans factors influencing mutation rate have been identified [1], such as chromatin remodelers, histone-modifying enzymes, and other DNA binding proteins [2][3][4]. In addition, replication timing [5][6][7][8][9] and transcription rate [10][11][12][13][14] also affect mutation rate.…”

Section: Introductionmentioning

confidence: 99%

DNA local structure decreases mutation rates

Duan

Huan

Chen³

et al. 2018

Preprint

Self Cite

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“…Genome-wide analysis in yeast has confirmed an enrichment of R-loops at highly transcribed regions [41-43]. Consistent with active transcription exposing the NTS as ssDNA, alterations in primary sequence that increase nascent RNA folding, which is predicted to reduce R-loop formation, mitigate TAM [44]. It should be noted, however, that direct evidence of an NTS-bias in the accumulation of endogenous DNA damage has not been reported in yeast.…”

Section: Transcription As a Source Of Genetic Instabilitymentioning

confidence: 99%

Ribonucleotides and Transcription-Associated Mutagenesis in Yeast

Cho

Jinks-Robertson

2017

Journal of Molecular Biology

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High levels of transcription stimulate mutation rates in microorganisms and this occurs primarily through an enhanced accumulation of DNA damage. The major source of transcription-associated damage in yeast is topoisomerase I (Top1), an enzyme that removes torsional stress that accumulates when DNA strands are separated. Top1 relieves torsional stress by nicking and re-sealing one DNA strand, and some Top1-dependent mutations are due to trapping and processing of the covalent cleavage intermediate. Most, however, reflect enzyme incision at ribonucleotides, which are the most abundant non-canonical component of DNA. In either case, Top1 generates a distinctive mutation signature comprised of short deletions in tandem repeats; in the specific case of ribonucleotide-initiated events, mutations reflect sequential cleavage by the enzyme. Top1-dependent mutations do not require highly activated transcription, but their levels are greatly increased by transcription, which partially reflects an interaction of Top1 with RNA polymerase. Recent studies have demonstrated that Top1-dependent mutations exhibit a strand bias, with the nature of the bias differing depending on the transcriptional status of the underlying DNA. Under low-transcription conditions, most Top1-dependent mutations arise in the context of replication and reflect incision at ribonucleotides incorporated during leading-strand synthesis. Under high-transcription conditions, most Top1-dependent events arise when the enzyme cleaves the non-transcribed strand of DNA. In addition to increasing genetic instability in growing cells, Top1 activity in transcriptionally active regions may be a source of mutations in quiescent cells.

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“…Generally, transcription is mutagenic and DNA damage is partly due to the R‐loop formed through the binding of the nascent RNA with its DNA template exposing the DNA nontemplate strand to mutagens and to primers that induce unscheduled error‐prone DNA synthesis . A recent study revealed that nascent RNA folding can mitigate transcription‐associated mutagenesis (Figure (b)) . The authors illustrated that heightening RNA folding and reducing R‐loop formation by synonymous changes in a reporter gene can lower the mutation rate immensely.…”

Section: Functions Of Rna Conformational Transitionsmentioning

confidence: 99%

“…21,49 A recent study revealed that nascent RNA folding can mitigate transcription-associated mutagenesis (Figure 2(b)). 50 The authors illustrated that heightening RNA folding and reducing R-loop formation by synonymous changes in a reporter gene can lower the mutation rate immensely. Over-expression of the gene RNase H1 can degrade the RNA in a DNA-RNA hybrid and decrease the effect, implying that it is R-loop dependent.…”

Section: Transcription Activation and Termination And Mutagenesismentioning

confidence: 99%

Regulatory effects of cotranscriptional RNA structure formation and transitions

Liu

Zhang

2016

WIREs RNA

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RNAs, which play significant roles in many fundamental biological processes of life, fold into sophisticated and precise structures. RNA folding is a dynamic and intricate process, which conformation transition of coding and noncoding RNAs form the primary elements of genetic regulation. The cellular environment contains various intrinsic and extrinsic factors that potentially affect RNA folding in vivo, and experimental and theoretical evidence increasingly indicates that the highly flexible features of the RNA structure are affected by these factors, which include the flanking sequence context, physiochemical conditions, cis RNA-RNA interactions, and RNA interactions with other molecules. Furthermore, distinct RNA structures have been identified that govern almost all steps of biological processes in cells, including transcriptional activation and termination, transcriptional mutagenesis, 5'-capping, splicing, 3'-polyadenylation, mRNA export and localization, and translation. Here, we briefly summarize the dynamic and complex features of RNA folding along with a wide variety of intrinsic and extrinsic factors that affect RNA folding. We then provide several examples to elaborate RNA structure-mediated regulation at the transcriptional and posttranscriptional levels. Finally, we illustrate the regulatory roles of RNA structure and discuss advances pertaining to RNA structure in plants. WIREs RNA 2016, 7:562-574. doi: 10.1002/wrna.1350 For further resources related to this article, please visit the WIREs website.

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Nascent RNA folding mitigates transcription-associated mutagenesis

Cited by 19 publications

References 58 publications

DNA local structure decreases mutation rates

DNA local structure decreases mutation rates

Ribonucleotides and Transcription-Associated Mutagenesis in Yeast

Regulatory effects of cotranscriptional RNA structure formation and transitions

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