RNA exosome-dependent transcriptional adaptation masks gene essentiality

Here, we show that RNA exosome-dependent buffering frequently masks knockout phenotypes. Using combinatorial CRISPR screens, we identify RNA exosome-dependent genes whose loss-of-function phenotypes are revealed only when RNA surveillance is impaired.

We find that the RNA exosome is required for both the initiation and maintenance of transcriptional adaptation, in which disruption of a trigger gene induces the compensatory upregulation of a buffering gene. Mechanistically, intronic Alu elements provide sequence homology between trigger-buffer gene pairs and regulate the formation of circular RNAs that suppress compensatory transcription. Disrupting splicing, deleting intronic Alu elements, or targeting the resulting circular RNAs reduces circular RNA abundance and enables transcriptional adaptation.