A stress‐activated, p38 MAPK‐ATF/CREB pathway regulates the post‐transcriptional decay of target mRNAs

Abstract

Broadly conserved, mitogen‐activated/stress‐activated protein kinases (MAPK/SAPK) of the p38 family regulate multiple cellular processes. They transduce signals via dimeric, basic leucine zipper (bZIP) transcription factors of the ATF/CREB family (such as Atf2, Fos and Jun) to regulate the transcription of target genes. We report that, upon stress, the fission yeast Spc1 kinase‐regulated Atf1‐Pcr1 heterodimer controls the post‐transcriptional decay of a set of target RNAs. Whole transcriptome RNA‐SEQ data revealed that decay is associated nonrandomly with transcripts that contain an M26 (CRE‐like) motif. Moreover, the ablation of an M26 site in a target mRNA is sufficient to block its stress‐induced decay. Conversely, engineered M26 sites can render an otherwise stable mRNA into an mRNA that is targeted for decay in their vicinity, demonstrating that the position of M26 site dictates where the transcript is cleaved. This post‐transcriptional, Stress‐Activated Gene Silencing (SAGS) provides a mechanism to reduce the expression of target genes without shutting off transcription itself. Thus, a single p38‐ATF/CREB signal transduction pathway can coordinately induce (promote transcription) and repress (SAGS) transcript levels for distinct sets of genes, as is required for developmental decisions in response to stress and other stimuli.