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Title: Transcriptional regulation of Fe-S biogenesis genes: a safeguard against arsenate toxicity

Speaker: Sofia Silva

Affiliation: Genomics and Stress Lab, ITQB NOVA

Abstract:

Arsenic (As) is a naturally occurring highly toxic metalloid, responsible for a variety of adverse health effects in humans, including carcinogenesis. In the eukaryotic model yeast Saccharomyces cerevisiae As detoxification is regulated by the transcription factors Yap8 and Yap1, two members of the Yap (Yeast AP-1 like) family. Yap8 is on the front line in what concerns the response to arsenic stress, as it is a potent regulator of the genes encoding Acr2, an arsenate (As(V)) reductase, and Acr3, an arsenite (As(III)) permease. Yap1 was previously shown to be involved in the mitigation of arsenic-generated reactive oxygen species, by regulating genes encoding several of the cellular antioxidant defenses. However, under anoxia conditions, cells lacking both regulators are more sensitive to arsenate than cells lacking each regulator individually, suggesting that Yap1 role in As detoxification is not restricted to the regulation of the oxidative stress response. This finding prompted us to study the transcriptomic profile of wild-type and yap1 mutant cells exposed to arsenate. Interestingly, we found that, under such conditions, several genes involved in the biogenesis of Fe-S proteins were upregulated in a Yap1-dependent way. In line with this observation, arsenate treatment decreases the activity of the mitochondrial aconitase, Aco1, an Fe-S cluster-containing enzyme, this effect being even more pronounced in the yap1 mutant. Reinforcing the relevance of Fe-S cluster biogenesis in arsenate detoxification, the overexpression of several ISC and CIA machinery genes alleviates the deleterious effect of arsenate caused by the absence of Yap1 and Yap8.

Altogether our data suggest that the upregulation of Fe-S biogenesis genes regulated by Yap1 might work as a cellular shield against arsenate toxicity.