Cytoplasmic mRNA decay by the antiviral nuclease RNase L promotes transcriptional repression

Ribonuclease (RNase) L is an antiviral factor that promiscuously degrades viral and cellular RNA in the cytoplasm. This results in extensive translational reprogramming, altering mRNA processing and export. Here, we reveal that another major consequence of cytoplasmic RNase L activity is the repression of nascent RNA synthesis in the nucleus. This is not associated with altered nuclear RNA stability but instead results from transcriptional repression. For RNA polymerase II, repression is primarily associated with reduced occupancy of serine-2-phosphorylated polymerase in gene bodies, indicating an elongation defect. Prominent among the transcriptionally downregulated loci are immune-related genes, supporting a role for RNase L in tempering innate immune and inflammatory responses. RNase L activation also caused disruption of nucleoli and reduced RNA polymerase I and III transcription. Crosstalk between RNA decay and transcription thereby contributes to the large-scale modulation of gene expression in RNase L-activated cells.