Journal
ELIFE
Volume 8, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.40260
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Funding
- National Institute of General Medical Sciences [T32GM008061, GM088290]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK115690]
- American Cancer Society [127313-RSG-15-135-01-DD]
- National Institute of Environmental Health Sciences [ES029930]
- Next Generation Fund
- Sherman-Fairchild Cancer Innovation Award
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We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology.
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