Transcription feedback dynamics in the wake of cytoplasmic degradation shutdown

In the last decade, multiple studies have shown that cells maintain a balance of mRNA production and degradation, but the mechanisms by which cells implement this balance remain unknown. Here, we monitored cells’ mRNA and nascent mRNA profiles immediately following an acute depletion of Xrn1 - the main 5’-3’ mRNA exonuclease - that was previously implicated in balancing mRNA levels. We captured the detailed dynamics of the cells’ adaptation to rapid degradation of Xrn1 and observed a significant accumulation of mRNA, followed by a delayed global reduction in nascent transcription and a gradual return to baseline mRNA levels. We present evidence that this transcriptional response is linked to cell cycle progression, and that it is not unique to Xrn1 depletion; rather, it is induced earlier when upstream factors in the 5’-3’ degradation pathway are perturbed. Our data suggest that the RNA feedback mechanism is cell-cycle-linked and monitors the accumulation of inputs to the 5’-3’ exonucleolytic pathway rather than its outputs.