RT Journal Article SR Electronic T1 Premature termination codons signal targeted gene repair by nonsense-mediated gene editing in E. coli JF bioRxiv FD Cold Spring Harbor Laboratory SP 069971 DO 10.1101/069971 A1 Xiaolong Wang A1 Xuxiang Wang A1 Haibo Peng A1 Chunyan Li A1 Gang Chen A1 Jianye Zhang A1 Michael Lynch YR 2018 UL http://biorxiv.org/content/early/2018/03/19/069971.abstract AB 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.