PT  - JOURNAL ARTICLE
AU  - Gokul, G
AU  - Singh, Jogender
TI  - Dithiothreitol causes toxicity in <em>C. elegans</em> by modulating the methionine-homocysteine cycle
AID  - 10.1101/2021.11.16.468906
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.16.468906
4099  - http://biorxiv.org/content/early/2021/11/17/2021.11.16.468906.short
4100  - http://biorxiv.org/content/early/2021/11/17/2021.11.16.468906.full
AB  - The redox reagent dithiothreitol (DTT) causes stress in the endoplasmic reticulum (ER) by disrupting its oxidative protein folding environment, which results in the accumulation and misfolding of the newly synthesized proteins. DTT may potentially impact cellular physiology by ER-independent mechanisms; however, such mechanisms remain poorly characterized. Using the nematode model Caenorhabditis elegans, here we show that DTT toxicity is modulated by the bacterial diet. Specifically, the dietary component vitamin B12 alleviates DTT toxicity in a methionine synthase-dependent manner. Using a forward genetic screen, we identify that loss-of-function of R08E5.3, an S-adenosylmethionine (SAM)-dependent methyltransferase, imparts resistance to DTT. DTT upregulates R08E5.3 expression and modulates the activity of the methionine-homocysteine cycle. Employing genetic studies, we show that DTT toxicity is a result of the depletion of SAM. Finally, we show that a functional IRE-1/XBP-1 unfolded protein response pathway is required to counteract toxicity at high, but not low, DTT concentrations.Competing Interest StatementThe authors have declared no competing interest.