LAUSR

Abstract Premature transcription termination is a critical mechanism for repressing harmful, unproductive transcription. In Saccharomyces cerevisiae, premature termination by the Nrd1–Nab3–Sen1 (NNS) complex also triggers decay of mRNAs induced to counteract stress. However, why mRNAs might be upregulated and simultaneously targeted for degradation remains unclear. Our work reveals a novel role for NNS as a gene expression noise suppression system. Single-cell analyses demonstrate that targeted disruption of Nab3 binding to the highly conserved mitochondrial transporter PIC2 not only alters its mRNA stability and protein levels but also dramatically increases cell-to-cell variability in Pic2 protein concentration. This specific perturbation in the regulation of a low-abundant transcript has substantial phenotypic consequences: significantly increased cell volumes, disrupted energy homeostasis, decreased growth rate, and altered expression of other NNS-regulated genes—all of which highlight the physiological importance of NNS control of Pic2 protein concentration. We show further that elevated levels of the human orthologue of Pic2, whose expression is tuned by the microRNA machinery, cause similar energy homeostasis defects, underscoring the evolutionary conservation of the tight regulation of the PIC2 gene. Our results illustrate that targeted changes in the interaction of a single transcription termination factor (Nab3) with a specific RNA substrate can trigger significant system-wide defects and profoundly impact cellular fitness.