title: Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney.
abstract: 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.
authors.affiliation: Departments of Biological Engineering and Biology, Center for Environmental Health Sciences, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ebrahimkhani
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129.
authors.forename: Ali
authors.initials: A
authors.lastname: Daneshmand
authors.affiliation: Departments of Biological Engineering and Biology, Center for Environmental Health Sciences, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Aprotim
authors.initials: A
authors.lastname: Mazumder
authors.affiliation: Departments of Biological Engineering and Biology, Center for Environmental Health Sciences, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Allocca
authors.affiliation: Departments of Biological Engineering and Biology, Center for Environmental Health Sciences, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Calvo
authors.affiliation: Departments of Biological Engineering and Biology, Center for Environmental Health Sciences, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Nona
authors.initials: N
authors.lastname: Abolhassani
authors.affiliation: Departments of Biological Engineering and Biology, Center for Environmental Health Sciences, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Iny
authors.initials: I
authors.lastname: Jhun
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, Stroke Service and Neuroscience Intensive Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Cenk
authors.initials: C
authors.lastname: Ayata
authors.affiliation: Departments of Biological Engineering and Biology, Center for Environmental Health Sciences, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; lsamson@mit.edu.
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D020520:Brain Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016923:Cell Death; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004790:Enzyme Induction / Q000235:genetics; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases
keywords: Aag/Mpg DNA glycosylase; DNA repair; base excision; ischemia reperfusion; liver