Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

Mohammad Ebrahimkhani, Ali Daneshmand, Aprotim Mazumder, Mariacarmela Allocca, Jennifer A. Calvo, Nona Abolhassani, Iny Jhun, Sureshkumar Muthupalani, Cenk Ayata, Leona D. Samson

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E4878-E4886
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number45
DOIs
StatePublished - Nov 11 2014
Externally publishedYes

Fingerprint

Reperfusion Injury
Reactive Nitrogen Species
DNA Repair
Reperfusion
Ischemia
Kidney
Reactive Oxygen Species
3-methyladenine-DNA glycosylase
Poisons
Liver
Brain
Inflammation
DNA Damage
Polymers
DNA Glycosylases
DNA Breaks
Poly(ADP-ribose) Polymerases
DNA
Cerebral Infarction
Nuclear Proteins

Keywords

  • Aag/Mpg DNA glycosylase
  • Base excision
  • DNA repair
  • Ischemia reperfusion
  • Liver

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney. / Ebrahimkhani, Mohammad; Daneshmand, Ali; Mazumder, Aprotim; Allocca, Mariacarmela; Calvo, Jennifer A.; Abolhassani, Nona; Jhun, Iny; Muthupalani, Sureshkumar; Ayata, Cenk; Samson, Leona D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 45, 11.11.2014, p. E4878-E4886.

Research output: Contribution to journalArticle

Ebrahimkhani, M, Daneshmand, A, Mazumder, A, Allocca, M, Calvo, JA, Abolhassani, N, Jhun, I, Muthupalani, S, Ayata, C & Samson, LD 2014, 'Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 45, pp. E4878-E4886. https://doi.org/10.1073/pnas.1413582111
Ebrahimkhani, Mohammad ; Daneshmand, Ali ; Mazumder, Aprotim ; Allocca, Mariacarmela ; Calvo, Jennifer A. ; Abolhassani, Nona ; Jhun, Iny ; Muthupalani, Sureshkumar ; Ayata, Cenk ; Samson, Leona D. / Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 45. pp. E4878-E4886.
@article{5bdabbd76d764d3fa796cc78c7aab445,
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.",
keywords = "Aag/Mpg DNA glycosylase, Base excision, DNA repair, Ischemia reperfusion, Liver",
author = "Mohammad Ebrahimkhani and Ali Daneshmand and Aprotim Mazumder and Mariacarmela Allocca and Calvo, {Jennifer A.} and Nona Abolhassani and Iny Jhun and Sureshkumar Muthupalani and Cenk Ayata and Samson, {Leona D.}",
year = "2014",
month = "11",
day = "11",
doi = "10.1073/pnas.1413582111",
language = "English (US)",
volume = "111",
pages = "E4878--E4886",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "45",

}

TY - JOUR

T1 - Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

AU - Ebrahimkhani, Mohammad

AU - Daneshmand, Ali

AU - Mazumder, Aprotim

AU - Allocca, Mariacarmela

AU - Calvo, Jennifer A.

AU - Abolhassani, Nona

AU - Jhun, Iny

AU - Muthupalani, Sureshkumar

AU - Ayata, Cenk

AU - Samson, Leona D.

PY - 2014/11/11

Y1 - 2014/11/11

N2 - 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.

AB - 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.

KW - Aag/Mpg DNA glycosylase

KW - Base excision

KW - DNA repair

KW - Ischemia reperfusion

KW - Liver

UR - http://www.scopus.com/inward/record.url?scp=84909592573&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84909592573&partnerID=8YFLogxK

U2 - 10.1073/pnas.1413582111

DO - 10.1073/pnas.1413582111

M3 - Article

VL - 111

SP - E4878-E4886

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 45

ER -