Coordinated regulation of mRNA translation and stability by ZC3H7A and ZC3H7B RNA-binding proteins

mRNA translation and stability are tightly regulated and functionally linked through cis-acting sequence elements and trans-acting factors, including RNA-binding proteins (RBPs). Here, we report that two chordate-specific paralogous RBPs, ZC3H7A and ZC3H7B, preferentially bind the coding region (CDS) and 3' untranslated region (3' UTR) of A/U-rich mRNAs, particularly those with enrichment of A/U at their wobble sites (A/U3 codons). Upon binding to target mRNAs, ZC3H7A/B promote mRNA degradation through recruitment of the CCR4-NOT deadenylase complex. Furthermore, these proteins engage ribosomes lacking elongation factors and repress translation initiation via the GIGYF2/4EHP translation repressor complex. Depletion of ZC3H7A/B or 4EHP impairs the translational repression of A/U3-rich mRNAs. Together, these findings reveal a mechanism in higher eukaryotes that links A/U-rich sequence content within the CDS and 3' UTR to the coordinated post-transcriptional regulation of mRNA stability and translation.