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 revealed that reverse mutations were caused not by random mutagenesis but by active targeted gene repair. Molecular studies suggest that the premature termination codons (PTCs) in nonsense mRNAs signal the repair of the frameshift mutation. Genome survey indicate that the genome sequence of a revertant is stable, confirmed that the revertant is not a mutator. 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 frameshift mutant promoted the gene 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 PTC signaling, edited by RNA editing and then used to direct the repair of their defective coding gene through mismatch repair and homologous recombination. In addition, this mechanism also serves as a novel driving force for molecular evolution, and the widespread existence of frameshift homologs within and across species is considered as evolutionary evidences preserved in nature.
