RT Journal Article
SR Electronic
T1 Natural variation in arsenic toxicity is explained by differences in branched chain amino acid catabolism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 373787
DO 10.1101/373787
A1 Stefan Zdraljevic
A1 Bennett W. Fox
A1 Christine Strand
A1 Oishika Panda
A1 Francisco J. Tenjo
A1 Shannon C. Brady
A1 Tim A. Crombie
A1 John G. Doench
A1 Frank C. Schroeder
A1 Erik C. Andersen
YR 2018
UL http://biorxiv.org/content/early/2018/07/24/373787.abstract
AB Organisms are often exposed to the environmentally ubiquitous toxic metalloid arsenic, and genetic differences unique to individuals can cause differential susceptibility to arsenic. To understand how molecular mechanisms of arsenic toxicity vary among individuals, we used two genetic mapping approaches to show that a major source of natural differences in Caenorhabditis elegans responses to arsenic trioxide is caused by variation in the dbt-1 gene. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) catabolism. We used CRISPR/Cas9-mediated genome editing to show that a single non-synonymous variant (C78S) in the highly conserved lipoyl domain of DBT-1 is the causal polymorphism underlying variation in response to arsenic trioxide. Using targeted metabolomics and chemical supplementation experiments, we demonstrate that differences in C. elegans responses to arsenic trioxide are caused by variation in the abundances of iso-branched chain fatty acids that serve a central role in developmental progression. We hypothesize that the presence of the additional thiol group in the sensitive DBT-1 C78 allele participates in arsenic binding, thereby more strongly inhibiting BCKDH function. We go on to show that branched chain fatty acids are affected after arsenic treatment of human cells. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across divergent individuals in human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of using C. elegans natural genetic diversity in combination with comparative metabolomics to identify mechanisms by which environmental toxins affect organismal physiology.