Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney
Name
Ebrahimkhani-2014-Aag-initiated base.pdf
Size
1.63 MB
Format
Adobe PDF
Checksum (MD5)
9f33ad95eb4f63cb9080e771d18ac198
Author(s)
Daneshmand, Ali
Mazumder, Aprotim
Allocca, Mariacarmela
Calvo, Jennifer A.
Abolhassani, Nona
Jhun, Iny
Muthupalani, Sureshkumar
Ayata, Cenk
Ebrahimkhani, Mohammad Reza
Samson, Leona D
Date Issued
October 2014
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences (U.S.)
Citation
Ebrahimkhani, Mohammad R., Ali Daneshmand, Aprotim Mazumder, Mariacarmela Allocca, Jennifer A. Calvo, Nona Abolhassani, Iny Jhun, Sureshkumar Muthupalani, Cenk Ayata, and Leona D. Samson. “Aag-Initiated Base Excision Repair Promotes Ischemia Reperfusion Injury in Liver, Brain, and Kidney.” Proceedings of the National Academy of Sciences 111, no. 45 (October 27, 2014): E4878–E4886.
Version
Final published version
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[superscript −/−] 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[superscript −/−] 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[superscript −/−] 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.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Division of Comparative Medicine
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1073/pnas.1413582111
