No-go decay dampens zinc finger protein mRNAs in vertebrates

Abstract Quality control of translation is crucial for maintaining cellular and organismal homeostasis. Obstacles in translation elongation induce ribosome collision, which is monitored by multiple sensor mechanisms. The E3 ubiquitin ligase ZNF598 recognizes collided ribosomes, triggering ribosome-associated quality control (RQC) to rescue stalled ribosomes and no-go decay (NGD) to degrade stall-prone mRNAs in eukaryotes. However, the role of RQC and NGD in maintaining the translational homeostasis of endogenous mRNAs has remained largely unclear. In this study, we investigated endogenous substrate mRNAs of NGD using the maternal-to-zygotic transition (MZT) of zebrafish embryos as a model system. Combining RNA-Seq analysis of znf598 mutant embryos with disome profiling and reporter assays, we revealed that mRNAs encoding the C2H2-type zinc finger domain (C2H2-ZF) frequently cause ribosome collisions and induce NGD during the MZT. Furthermore, we showed that mRNAs encoding C2H2-ZF are degraded by ZNF598 in human cells. Our results suggest that NGD maintains the quality of the translatome during protein evolution and animal development by mitigating the risk of ribosome collision at the abundantly present C2H2-ZF mRNA sequences.