Inflammation is accompanied by the release of highly reactive
oxygen and
nitrogen species (RONS) that damage
DNA, among other cellular molecules. Base excision repair (BER) is initiated by
DNA glycosylases and is crucial in repairing RONS-induced DNA damage; the
alkyladenine DNA glycosylase (Aag/Mpg) excises several
DNA base lesions induced by the
inflammation-associated RONS release that accompanies
ischemia reperfusion (I/R). Using mouse I/R models we demonstrate that Aag(-/-) mice are significantly protected against, rather than sensitized to, I/R injury, and that such protection is observed across three different organs. Following I/R in liver, kidney, and brain, Aag(-/-) mice display decreased hepatocyte death,
cerebral infarction, and renal injury relative to wild-type. We infer that in wild-type mice, Aag excises damaged
DNA bases to generate potentially toxic abasic sites that in turn generate highly toxic
DNA strand breaks that trigger
poly(ADP-ribose) polymerase (Parp) hyperactivation, cellular bioenergetics failure, and
necrosis; indeed, steady-state levels of abasic sites and nuclear PAR
polymers were significantly more elevated in wild-type vs. Aag(-/-) liver after I/R. This increase in PAR
polymers was accompanied by depletion of intracellular
NAD and
ATP levels plus the translocation and extracellular release of the high-mobility group box 1 (
Hmgb1)
nuclear protein, activating the sterile inflammatory response. We thus demonstrate the detrimental effects of Aag-initiated BER during I/R and sterile
inflammation, and present a novel target for controlling I/R-induced injury.