The roles of the RNA-binding proteins ZC3H7A and ZC3H7B in the post-transcriptional regulation of gene expression

Abstract

Reduced translation elongation rate due to the presence of non-optimal codons can negatively affect the stability of mRNA through translation-dependent mRNA decay pathways. However, the mechanism(s) that sense the optimality of the codons in mRNA to regulate their stability remains poorly understood. In this thesis, I identify a role for two paralog RBPs; ZC3H7A and ZC3H7B, which are ubiquitously expressed across human tissues; in translation-dependent regulation of mRNA stability in mammalian cells.

PAR-CLIP analysis of ZC3H7A and ZC3H7B target RNAs in HEK293 cells showed a high degree of similarity in their binding patterns, with the proteins predominantly interacting with mRNAs at their CDS and 3´ UTR. Moreover, by performing parallel RNA-seq and Ribo-seq analyses, I observed a clear negative correlation between the number of binding sites and the changes in mRNA abundance, suggesting the binding of ZC3H7 proteins result in the degradation of the target mRNAs. Further analysis of ZC3H7A and ZC3H7B target mRNAs revealed a clear preference for their binding to A/U-rich transcripts, which are enriched with non-optimal A/U3 codons in their CDS. I also found that the typical relationship between codon usage and mRNA stability is perturbed upon depletion of the ZC3H7A and ZC3H7B proteins.
I propose that ZC3H7A/B sense codon optimality through interactions with ribosomes while they are not actively translating, and induce mRNA decay through recruitment of the CCR4-NOT complex.

Thesis is embargoed until 31 July 2031.

Date of Award	Jul 2026
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	BBSRC
Supervisor	Seyed Mehdi Jafarnejad (Supervisor) & Sarah Maguire (Supervisor)