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Premature termination codons signal targeted gene repair by nonsense-mediated gene editing in E. coli

Xiaolong Wang, Xuxiang Wang, Haibo Peng, Chunyan Li, Gang Chen, Jianye Zhang, Michael Lynch
doi: https://doi.org/10.1101/069971
Xiaolong Wang
College of Life Sciences, Ocean University of China, Qingdao, 266003, P. R. China
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  • For correspondence: Xiaolong@ouc.edu.cn
Xuxiang Wang
College of Life Sciences, Ocean University of China, Qingdao, 266003, P. R. China
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Haibo Peng
College of Life Sciences, Ocean University of China, Qingdao, 266003, P. R. China
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Chunyan Li
College of Life Sciences, Ocean University of China, Qingdao, 266003, P. R. China
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Gang Chen
College of Life Sciences, Ocean University of China, Qingdao, 266003, P. R. China
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Jianye Zhang
College of Life Sciences, Ocean University of China, Qingdao, 266003, P. R. China
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Michael Lynch
Center for Mechanisms of Evolution, BioDesign Institute, Arizona State University, Tempe, AZ, 85287-7701
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Abstract

Frameshift mutations yield truncated proteins, leading to loss-of-function, genetic disorders or even death. Reverse mutations, which restore the wild-type phenotype of a mutant, have been assumed to be far rarer than forward mutations. However, in this study, screening tests showed that the revertants of a frameshift mutation are detected more frequently than expected in E. coli. Sanger sequencing of the revertants revealed that the reversion of the frameshift mutation is not caused by random mutagenesis but by active targeted gene repair. Molecular studies suggest that premature termination codons (PTCs) in the nonsense mRNAs signal the repair of the frameshift mutation. Genome survey indicate that the genome sequence of a revertant is stable, confirming that the DNA replication proofreading/mismatch repair system of the revertant is not defective. Transcriptome profiling identified dozens of upregulated genes/pathways that possibly involve in frameshift repair, including DNA replication, RNA processing, RNA editing, mismatch repair and homologous recombination. Introducing synthetic DNA or RNA oligonucleotides into the frameshift can promote the gene repair. Based on these data and an in-depth review of previous studies, we hypothesized a molecular model for frameshift repair referred to as nonsense-mediated gene editing (NMGE): nonsense mRNAs are recognized by mRNA surveillance by PTC signaling, edited by RNA editing and then used to direct the repair of their defective coding gene through mismatch repair and homologous recombination. Moreover, NMGE may also serve as a driving force for molecular evolution and a new source of genetic diversity, leads to a widespread existence of frameshift homologs.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 19, 2018.
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Premature termination codons signal targeted gene repair by nonsense-mediated gene editing in E. coli
Xiaolong Wang, Xuxiang Wang, Haibo Peng, Chunyan Li, Gang Chen, Jianye Zhang, Michael Lynch
bioRxiv 069971; doi: https://doi.org/10.1101/069971
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Premature termination codons signal targeted gene repair by nonsense-mediated gene editing in E. coli
Xiaolong Wang, Xuxiang Wang, Haibo Peng, Chunyan Li, Gang Chen, Jianye Zhang, Michael Lynch
bioRxiv 069971; doi: https://doi.org/10.1101/069971

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