November 2025, Granneman lab, Nucleic Acids Research Authors Esteban-Serna, S., Widén, T., Gwynne, M., Farquhar, I., Duchen, M.R., Swain, P.S., and Granneman, S. Summary By Cristina Cardenal-Peralta, Proteomics Core, DRP-HCBNNS complex, transcription termination, RNA decay, PIC2 regulation, stress-induced gene expression.Cells respond to stress by rapidly reprogramming gene expression, with transcription termination playing a key regulatory role in shifting from basal to stress-induced programmes. In Saccharomyces cerevisiae, the NNS complex mediates premature termination of select transcripts and promotes their degradation, creating a mechanism to fine-tune gene output.The Granneman group hypothesised that stress-induced genes are concurrently targeted by NNS to prevent excessive expression during nutrient limitation. They focused on PIC2, which is strongly upregulated during glucose starvation and conserved via its mammalian homologue SLC25A3. Mutation of NNS-binding motifs within PIC2 resulted in a 2–4-fold increase in mRNA levels, confirming that NNS normally dampens its expression.Transcriptome-wide RNA-seq revealed that disrupting PIC2–NNS interactions had broader consequences, altering the stability of 488 transcripts. This was supported by CRAC data analysis using DBPeaks, which identified widespread redistribution of NNS binding across the transcriptome. Thus, perturbing a single NNS target can rewire global RNA regulation.Functionally, loss of NNS control over PIC2 led to increased protein levels and greater cell-to-cell variability, alongside clear phenotypic defects: enlarged cell size, reduced growth rate, and disrupted homeostasis. These findings demonstrate that NNS-mediated regulation not only buffers expression of individual stress-induced genes but also coordinates a wider network. Overall, the data support a model in which transcription termination acts as a global regulatory hub, ensuring balanced, homogeneous, and adaptive gene expression under stress conditions. The Nrd1-Nab3-Sen1 transcriptional termination complex attenuates the expression and protein concentration of a stress-responsive protein-coding gene (PIC2), improving cell fitness and adaptability to environmental challenges. Preventing the binding of one of the proteins of the NNS complex to PIC2 impairs premature termination of the mRNA, elicits severe defects in cell growth, increases cell size and intracellular stress, and prolongs the cell cycle. We show that creating an imbalance in the RNA recognition of Nab3 and Nrd1 in PIC2 mRNA disturbs the homeostasis of co-regulated transcripts and aggravates the defects caused by suboptimal expression of PIC2. Related Links Journal URLPI WebsiteDOI This article was published on Wednesday 10 June 2026
