eIF5A coordinates the transcription and translation of its target genes

Abstract Maintaining balanced cellular protein levels requires precise control of gene expression and effective coordination between the various stages of the process, from transcription to translation. In recent years, several components of the translation apparatus have been found in the nuclei of various eukaryotes, where they regulate transcription, mRNA processing or export, thereby integrating different stages of gene expression. eIF5A is an essential and evolutionarily conserved translation elongation factor that is involved in viral infection and in the development of diseases such as cancer and neurodevelopmental disorders. eIF5A promotes translation elongation by binding to ribosomes that stall at codons encoding problematic amino acids for peptide bond formation, such as consecutive prolines, also known as polyproline motifs. Although eIF5A shuttles between the nucleus and cytoplasm, its specific nuclear roles remain poorly defined. Here, we demonstrate that nuclear yeast eIF5A binds to chromatin and represses gene transcription by preventing the binding of RNA polymerase II. Importantly, chromatin binding and transcriptional repression by eIF5A have a higher impact on genes encoding its own translational targets. The presence of polyproline motifs in genes imposes both translation and transcriptional control by eIF5A. Furthermore, eIF5A’s active engagement in cytoplasmic translation is necessary for its role in repressing transcription. Our results suggest that eIF5A coordinates gene expression by promoting the cytoplasmic translation of specific genes while repressing their transcription in the nucleus, thus ensuring efficient final protein synthesis. Significance Statement Our study provides genome-wide and gene-specific evidence supporting the role of the translation elongation factor eIF5A in transcription. eIF5A is essential in eukaryotes, facilitating the translation of mRNAs encoding stretches of problematic amino acids, such as consecutive prolines. Through its role in the synthesis of specific proteins, eIF5A has been linked to development and different diseases, including cancer and diabetes. We have now discovered that eIF5A also controls the transcription of its translation target genes and this effect is driven by the presence of eIF5A-dependent motifs at their sequences. In the nucleus, eIF5A binds to specific genes and attenuates the binding of RNA polymerase II. By negatively regulating transcription and positively regulating translation, eIF5A coordinates gene expression, fine-tuning protein levels. Competing Interest Statement The authors have declared no competing interest. Footnotes Competing Interest Statement: The authors declare that they have followed the uniform requirements for manuscripts submitted to Biomedical journals. The authors declare no conflict of interest.