TY - JOUR T1 - Premature termination codons signaled targeted gene repair by nonsense mRNA-mediated gene editing in <em>E. coli</em> JF - bioRxiv DO - 10.1101/069971 SP - 069971 AU - Xiaolong Wang AU - Haibo Peng AU - Chunyan Li AU - Xuxiang Wang AU - Gang Chen AU - Jianye Zhang Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/05/069971.abstract N2 - 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, was assumed to be far rarer than forward mutations. However, in this study, screening tests showed that the revertants of a frameshift mutation were detected more frequently than expected in E. coli. Sanger sequencing revealed that reverse mutations were caused not by random mutagenesis but by active targeted gene repair. Molecular studies suggested that it was the premature termination codons (PTCs) in nonsense mRNAs that signaled the repair of the frameshift mutation. Genome survey indicated that the genome sequence of a revertant is not more variable than that of a wild-type strain. Transcriptome profiling identified differentially expressed genes and pathways that were upregulated in frameshift or revertant which possibly involved in frameshift repair, include DNA replication, RNA surveillance, RNA editing, mismatch repair and homologous recombination. Introducing synthetic DNA or RNA oligonucleotides into the mutant increased the recovery rates as they promoted the frameshift repair. Based on these data, we hypothesized a molecular model for frameshift repair referred to as nonsense mRNA-mediated gene editing (NMGE): nonsense mRNAs were recognized by mRNA surveillance by PTCs signaling, edited by RNA editing and used to direct the repair of their defective coding gene through mismatch repair and homologous recombination. In addition, this mechanism also serve as a driving force for molecular evolution and the widespread presence of frameshift homologs within and across species is considered as evolutionary evidences preserved in nature. ER -