Document Detail

8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair.
MedLine Citation:
PMID:  23143307     Owner:  NLM     Status:  MEDLINE    
8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2'-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.
Zijing Sheng; Sugako Oka; Daisuke Tsuchimoto; Nona Abolhassani; Hiroko Nomaru; Kunihiko Sakumi; Hidetaka Yamada; Yusaku Nakabeppu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4344-61     Citation Subset:  AIM; IM    
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
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MeSH Terms
Apoptosis Inducing Factor / metabolism
Benzamides / pharmacology
Calpain / antagonists & inhibitors,  metabolism
Cell Nucleus / metabolism
Corpus Striatum / pathology
DNA Breaks, Single-Stranded
DNA Glycosylases / genetics,  metabolism,  physiology*
DNA Repair*
DNA, Mitochondrial / genetics
Dipeptides / pharmacology
Guanine / analogs & derivatives*,  metabolism,  physiology
Mice, Inbred C57BL
Mice, Knockout
Microglia / metabolism
Mitochondria / metabolism
Motor Activity
Neurodegenerative Diseases / etiology,  metabolism*,  pathology
Nitro Compounds
Oxidative Stress*
Phosphoric Monoester Hydrolases / genetics
Poly(ADP-ribose) Polymerases / antagonists & inhibitors,  metabolism
Reg. No./Substance:
0/Apoptosis Inducing Factor; 0/Benzamides; 0/DNA, Mitochondrial; 0/Dipeptides; 0/Nitro Compounds; 0/Pdcd8 protein, mouse; 0/Propionates; 3544-24-9/3-aminobenzamide; 504-88-1/3-nitropropionic acid; 5614-64-2/8-hydroxyguanine; 73-40-5/Guanine; 88191-84-8/calpain inhibitor III; EC protein, mouse; EC Polymerases; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.6.-/MTH1 protein, mouse; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.-/Ogg1 protein, mouse; EC 3.2.2.-/mutY adenine glycosylase; EC 3.4.22.-/Calpain

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