Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase

Endres, Matthias; Biniszkiewicz, Detlev; Sobol, Robert W.; Harms, Christoph; Ahmadi, Michael; Lipski, Andreas; Katchanov, Juri; Mergenthaler, Philipp; Dirnagl, Ulrich; Wilson, S.H.; Meisel, Andreas; Jaenisch, Rudolf

doi:10.1172/jci200420926

Cited by 105 publications

(70 citation statements)

References 37 publications

(25 reference statements)

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“…When a panoply of damaged bases is induced, base excision by Aag, in contrast to that by Ung, Neil1, and Ogg1, may exceed the capacity for the downstream BER enzymes to complete repair, thus generating toxic BER intermediates and cell death. Consequently, when Ung, Ogg1, or Neil1 are deficient, their unrepaired substrates become subject to Aag-initiated BER such that in the Ung/Ogg1/Neil1-deficient mice, Aag has even more substrates to repair, causing increased I/R-mediated tissue damage (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, it was shown that Parp1 has specific affinity to AP sites and 5′-dRP intermediates that are generated during BER initiated by monofunctional glycosylases (43,44), and excessive Parp1 activation is known to elicit necrotic cell death (16,18,19). Therefore, repair by Aag, a monofunctional glycosylase with an unusually broad range of substrates, may generate excessive amounts of BER intermediates and, in particular, highly toxic dRP intermediates, possibly explaining why Aag-initiated BER is toxic and Ung/Ogg1/Neil1 initiated repair is not (34)(35)(36). We previously observed that Aag −/− mice are more susceptible than WT mice to inflammation-associated colon cancer (12); this may at first appear to contradict the findings reported here.…”

Section: Discussionmentioning

confidence: 99%

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

Ebrahimkhani

Daneshmand

Mazumder

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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.DNA repair | base excision | Aag/Mpg DNA glycosylase | ischemia reperfusion | liver

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Ebrahimkhani

Daneshmand

Mazumder

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Generation of UNG-deficient mice, was previously described [38]. The Ung null allele was back-crossed for more than 10 generations onto a C57BL/6 background.…”

Section: Animal Diets and Experimental Designmentioning

confidence: 99%

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

Jadavji

Farr

Lips

et al. 2015

Behavioural Brain Research

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(2015) Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. Behavioural Brain Research, 283 . pp. 215-226. ISSN 1872-7549 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/32983/9/UNG_FADD_20140826_manuscript_final.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial No Derivatives licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc-nd/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil-DNA glycosylase impair learning in a mouse model of vascular cognitive impairment. ABSTRACTDietary deficiencies in folic acid result in elevated levels of plasma homocysteine, which has been associated with the development of dementia and other neurodegenerative disorders.Previously, we have shown that elevated levels of plasma homocysteine in mice deficient for a DNA repair enzyme, uracil-DNA glycosylase (UNG), result in neurodegeneration. The goal of this study was to evaluate how deficiencies in folic acid and UNG along with elevated levels of homocysteine affect vascular cognitive impairment, via chronic hypoperfusion in an animal model. Ung+/+ and Ung−/− mice were placed on either control (CD) or folic acid deficient (FADD) diets. Six weeks later, the mice either underwent implantation of microcoils around both common carotid arteries. Post-operatively, behavioral tests began at 3-weeks, angiography was measured after 5-weeks using MRI to assess vasculature and at completion of study plasma and brain tissue was collected for analysis. Learning impairments in the Morris water maze (MWM) were observed only in hypoperfused Ung−/− FADD mice and these mice had significantly higher plasma homocysteine concentrations. Interestingly, Ung+/+ FADD produced significant remodeling of the basilar artery and arterial vasculature. Increased expression of GFAP was observed in the dentate gyrus of Ung−/− hypoperfused and FADD sham mice. Chronic hypoperfusion resulted in increased cortical MMP-9 protein levels of FADD hypoperfused mice regardless of genotypes. These results suggest that elevated levels of homocysteine only, as a result of dietary folic acid deficiency, don't lead to memory impairments and neurobiochemical changes. Rather a combination of either chronic hypoperfusion o...

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“…46 However, UNG2 has not been co-purified with CENP-A, and like CENP-B, is not essential in mice. 95,96 Backup enzymatic activity was invoked to explain why UNG2 is not essential during development, but not all of the double and triple null mice have been made to test that explanation. 97 Second, looking further upstream, a cytidine deaminase (implicated by chemical inhibition 46 ) may provide specificity,…”

Section: Escape From Alcatraz: Evidence For Selective Stabilization Amentioning

confidence: 99%

Centromeres: The wild west of the post-genomic age

Zeitlin¹

2010

Epigenetics

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Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase

Cited by 105 publications

References 37 publications

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

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

Elevated levels of plasma homocysteine, deficiencies in dietary folic acid and uracil–DNA glycosylase impair learning in a mouse model of vascular cognitive impairment

Centromeres: The wild west of the post-genomic age

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