Cytoplasmic mRNA decay by the anti-viral nuclease RNase L promotes transcriptional repression

Ribonuclease (RNase) L is an antiviral factor that promiscuously degrades viral and cellular RNA in the cytoplasm. This causes extensive translational reprogramming and alters 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 a global loss of RNA polymerase II (Pol II) occupancy across the genome. Prominent among the transcriptionally downregulated loci are immune-related genes, supporting a role for RNase L in tempering innate immune and inflammatory responses. These transcriptional changes are associated with reduced levels and altered localization of a portion of serine 5-phosphorylated Pol II into nuclear speckles. Crosstalk between RNA decay and transcription thereby contributes to the large-scale modulation of gene expression in RNase L-activated cells.