A combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in Escherichia coli

Significance Class-II fumarases have been shown to participate in cellular respiration and the DNA damage response. Here, we show that in the model prokaryote, Escherichia coli , which harbors both class-I and class-II fumarases, it is the class-I fumarases that participate in DNA damage repair by a mechanism that is different from those described for other fumarases. Strikingly, this mechanism employs a signaling molecule, alpha-ketoglutarate (α-KG), and its target is the DNA damage repair enzyme AlkB. In addition, we show that the fumarase precursor metabolites, fumarate and succinate, can inhibit the α-KG–dependent DNA damage repair enzyme, AlkB, both in vitro and in vivo. This study provides a perspective on the function and evolution of metabolic signaling.