Journal
G3-GENES GENOMES GENETICS
Volume 8, Issue 12, Pages 3857-3863Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/g3.118.200727
Keywords
C. elegans; NHR-49; oxidative stress; reactive oxygen species; SKN-1
Categories
Funding
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- National Institutes of Health [DK068429, GM082971]
- Ontario Graduate Scholarship
- Natural Sciences and Engineering Research Council of Canada
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK068429, R56DK068429] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM082971] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [P40OD010440] Funding Source: NIH RePORTER
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The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegansBRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of nhr-49 promote gst-4 expression. We also demonstrate that nhr-49 and its cofactor mdt-15 are required to express phase II detoxification enzymes upon exposure to chemicals that induce oxidative stress. Furthermore, we show that NHR-49 and MDT-15 enhance expression of skn-1a/c. These findings identify a novel role for NHR-49 in ROS detoxification by regulating expression of SKN-1C and phase II detoxification genes.
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