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Rual, Jean-Francois

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Rual

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Jean-Francois

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Rual, Jean-Francois
Author's Publications: search.filters.isAuthorOfPublication.48835164-c55b-4480-b933-2b57f78f8d2a

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    RNAi Screening Implicates a SKN-1–Dependent Transcriptional Response in Stress Resistance and Longevity Deriving from Translation Inhibition
    (Public Library of Science, 2010) Wang, Jinling; Robida-Stubbs, Stacey; Tullet, Jennifer M. A.; Rual, Jean-Francois; Vidal, Marc; Blackwell, Thomas
    Caenorhabditis elegans SKN-1 (ortholog of mammalian Nrf1/2/3) is critical for oxidative stress resistance and promotes longevity under reduced insulin/IGF-1–like signaling (IIS), dietary restriction (DR), and normal conditions. SKN-1 inducibly activates genes involved in detoxification, protein homeostasis, and other functions in response to stress. Here we used genome-scale RNA interference (RNAi) screening to identify mechanisms that prevent inappropriate SKN-1 target gene expression under non-stressed conditions. We identified 41 genes for which knockdown leads to activation of a SKN-1 target gene (gcs-1) through skn-1-dependent or other mechanisms. These genes correspond to multiple cellular processes, including mRNA translation. Inhibition of translation is known to increase longevity and stress resistance and may be important for DR–induced lifespan extension. One model postulates that these effects derive from reduced energy needs, but various observations suggest that specific longevity pathways are involved. Here we show that translation initiation factor RNAi robustly induces SKN-1 target gene transcription and confers skn-1-dependent oxidative stress resistance. The accompanying increases in longevity are mediated largely through the activities of SKN-1 and the transcription factor DAF-16 (FOXO), which is required for longevity that derives from reduced IIS. Our results indicate that the SKN-1 detoxification gene network monitors various metabolic and regulatory processes. Interference with one of these processes, translation initiation, leads to a transcriptional response whereby SKN-1 promotes stress resistance and functions together with DAF-16 to extend lifespan. This stress response may be beneficial for coping with situations that are associated with reduced protein synthesis.
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    Novel Insights into RNAi Off-Target Effects Using C. elegans Paralogs
    (BioMed Central, 2007) Rual, Jean-Francois; Klitgord, Niels; Achaz, Guillaume
    Background: In the few years since its discovery, RNAi has turned into a very powerful tool for the study of gene function by allowing post-transcriptional gene silencing. The RNAi mechanism, which is based on the introduction of a double-stranded RNA (dsRNA) trigger whose sequence is similar to that of the targeted messenger RNA (mRNA), is subject to off-target cross-reaction. Results: We use a novel strategy based on phenotypic analysis of paralogs and predict that, in Caenorhabditis elegans, off-target effects occur when an mRNA sequence shares more than 95% identity over 40 nucleotides with the dsRNA. Interestingly, our results suggest that the minimum length necessary of a high-similarity stretch between a dsRNA and its target in order to observe an efficient RNAi effect varies from 30 to 50 nucleotides rather than 22 nucleotides, which is the length of siRNAs in C. elegans. Conclusion: Our predictive methods would improve the design of dsRNA and ultimately the use of RNAi as a therapeutic tool upon experimental verification.