Tissue-Specific Regulation of Translational Readthrough Tunes Functions of the Traffic Jam Transcription Factor

Summary Translational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR is pervasive in eukaryotic organisms; however, its biological significance remains unclear. In this study, we quantify the TR potential of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). We used CRISPR/Cas9 generated mutant flies to show that the TR-generated Tj isoform is expressed in the nuclei of a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads, which express the short Tj isoform only. Translational control of TR is critical for preservation of neuronal integrity and maintenance of reproductive health. Fine-tuning of the gene regulatory functions of transcription factors by TR provides a new potential mechanism for cell-specific regulation of gene expression. Highlights Tj undergoes tissue-specific TR in neural cells of the central nervous system. Strict control of TR is crucial for neuroprotection and maintenance of reproductive capacity. TR selectively fine-tunes the gene regulatory functions of the transcription factor. TR in Tj links transcription and translation of tissue-specific control of gene expression.