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

Abstract

Class-II fumarase (Fumarate Hydratase, FH) and its metabolic intermediates are essential components in the DNA damage response (DDR) in eukaryotic cells (human and yeast) and in the prokaryote Bacillus subtilis. Strikingly, here we show, in Escherichia coli, which harbors three fumarase genes; Class-I fumA and fumB and Class-II fumC, a variation of the distribution of function so far demonstrated (TCA cycle and DDR). Contrary to previous reports, E. coli Class-II fumarase participates naturally in respiration and the Class-I fumarases in the DDR. Contrary to other organisms, in E. coli, alpha-ketoglutarate (α-KG) is the organic acid that complements DNA damage sensitivity of fum null mutants. We show inhibition of the α-KG-dependent DNA damage repair enzyme, AlkB, by fumarate and succinate, and a global effect of fumarase absence on transcription. Together these results show an adaptable metabolic signalling of the DDR during evolution regardless of the enzyme Class preforming the DDR related function.