CCR4-NOT subunit CCF-1/CNOT7 promotes transcriptional activation to multiple stress responses in Caenorhabditis elegans

Abstract

CCR4-NOT is a versatile eukaryotic protein complex that controls multiple steps in gene expression regulation from synthesis to decay. In yeast, CCR4-NOT has been implicated in stress response regulation, though this function in other organisms remains unclear. In a genome-wide RNAi screen, we identified a subunit of the CCR4-NOT complex, ccf-1, as a requirement for the C. elegans transcriptional response to cadmium and acrylamide stress. Using whole-transcriptome RNA sequencing, we show that the knockdown of ccf-1 attenuates the activation of a broad range of stress-protective genes in response to cadmium and acrylamide, including those encoding heat shock proteins and xenobiotic detoxification. Consistently, survival assays show that the knockdown of ccf-1 decreases C. elegans stress resistance and normal lifespan. A yeast 2-hybrid screen using a CCF-1 bait identified the homeobox transcription factor PAL-1 as a physical interactor. Knockdown of pal-1 inhibits the activation of ccf-1 dependent stress genes and reduces C. elegans stress resistance. Gene expression analysis reveals that knockdown of ccf-1 and pal-1 attenuates the activation of elt-2 and elt-3 under stress that encode master transcriptional co-regulators of stress response in the C. elegans, and that overexpression of ELT-2 can suppress ccf-1's requirement for gene transcription in a stress-dependent manner. Our findings reveal a new role for CCR4-NOT in the environmental stress response and define its role in stress resistance and longevity in C. elegans.

Keywords: C. elegans; aging; longevity; oxidative stress; stress response.