Premature Termination Codon-Bearing mRNA Mediates Genetic Compensation Response

The genetic compensation response (GCR), triggered by deleterious mutations but not by gene knockdown, has been proposed to explain many phenotypic discrepancies between gene-knockout and gene-knockdown models. GCRs have been observed in many model organisms from mice to Arabidopsis. Although the GCR is beneficial for organism survival, it impedes the exploration of gene function as many knockout mutants do not display discernible phenotypes due to the GCR. Uncovering how the mechanism of GCR operates is not only a fundamental goal in biology but also may provide a key solution in the unmasking of phenotypes in mutants displaying GCRs. Using zebrafish as the model, two recent studies have provided a molecular basis to explain this genetic paradox by demonstrating that the nonsense-mediated mRNA decay pathway is essential for nonsense mRNA to upregulate the expression of its homologous genes through an enhancement of histone H3 Lys4 trimethylation (H3K4me3) at the transcription start site regions of the compensatory genes. Here, we summarize the progress on the molecular mechanism of the GCR and make suggestions on how to overcome GCRs in the generation of genetic mutants.