Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response

Sneha Rath; Eliza Prangley; Jesse Donovan; Kaitlin Demarest; Yigal Meir; Ned Wingreen; Alexei Korennykh

The log-linear decay of basal mRNAs indicates that 2-5AMD degrades these transcripts with single-exponential kinetics. In contrast, the log-linear increase of IFN/ISG mRNAs does not match single-exponential accumulation or steady influx laws, and indicates induction with a positive feedback ( The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/484675 doi: bioRxiv preprint from 2-5AMD. In contrast, protection is observed once a stable activator is included in the positive feedback loop (Fig. 7C ). The protection arises from the inherent resistance of proteins (IFNs, phosphorylated STAT) to RNase L. IFN proteins steadily accumulate and promote increasing transcriptional activity even in the presence of 2-5AMD. The evasion from 2-5AMD is further enhanced once 2.6-fold greater mRNA stability is incorporated in the model (Fig. 7D ). Our modeling results show that longer half-lives of defense mRNAs, as well as, independently, a positive feedback loop built around a stable activator can result in evasion of defense mRNAs from global decay.