Base excision repair capacity in mitochondria and nuclei: tissue‐specific variations

Karahalıl, Bensu; Hogue, Barbara A.; Souza-Pinto, Nadja C. de; Bohr, Vilhelm A.

doi:10.1096/fj.02-0463com

Cited by 103 publications

(73 citation statements)

References 34 publications

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“…Our measurements in these tissues will disproportionately reflect the activities of highly differ- Narciso et al (2007) demonstrated that a significant reduction in BER capacity occurs during differentiation of actively mitotic skeletal muscle progenitors (myoblasts) to post-mitotic myotubes (myofiber-like). Other authors have shown that BER enzyme activities are upregulated at specific times during the cell cycle (Chaudhry 2007) and are generally elevated in tissues containing higher proportions of actively mitotic cells (see Karahalil et al 2002). Perhaps the expected correlations of DNA repair activities with MLSP manifest in actively mitotic cells.…”

Section: Discussionmentioning

confidence: 95%

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

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Stuart

2011

AGE

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Accumulation of DNA lesions compromises replication and transcription and is thus toxic to cells. DNA repair deficiencies are generally associated with cellular replicative senescence and premature aging syndromes, suggesting that efficient DNA repair is required for normal longevity. It follows that the evolution of increasing lifespan amongst animal species should be associated with enhanced DNA repair capacities. Although UV damage repair has been shown to correlate positively with mammalian species lifespan, we lack similar insight into many other DNA repair pathways, including base excision repair (BER). DNA is continuously exposed to reactive oxygen species produced during aerobic metabolism, resulting in the occurrence of oxidative damage within DNA. Shortpatch BER plays an important role in repairing the resultant oxidative lesions. We therefore tested whether an enhancement of BER enzyme activities has occurred concomitantly with the evolution of increased maximum lifespan (MLSP). We collected brain and liver tissue from 15 vertebrate endotherm species ranging in MLSP over an order of magnitude. We measured apurinic/ apyrimidinic (AP) endonuclease activity, as well as the rates of nucleotide incorporation into an oligonucleotide containing a single nucleotide gap (catalyzed by BER polymerase β) and subsequent ligation of the oligonucleotide. None of these activities correlated positively with species MLSP. Rather, nucleotide incorporation and oligonucleotide ligation activities appeared to be primarily (and negatively) correlated with species body mass.

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Section: Discussionmentioning

confidence: 95%

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

Page

Stuart

2011

AGE

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“…However, further studies are required to address the question of whether this regulation of OGG1 activity coincides with the microclimate of the proliferation status of individual cell populations. Despite the high load of oxidative stress in the brain, adult mice have relatively low levels of OGG1 (Karahalil et al, 2002), which is upregulated after forebrain ischaemia reperfusion (Lin et al, 2000). A leading theory regarding ageing and ageing-related diseases, such as Alzheimer's disease (AD), involves free-radical-mediated oxidative stress in neuronal degeneration.…”

Section: Discussionmentioning

confidence: 99%

Repair and mutagenesis at oxidized DNA lesions in the developing brain of wild-type and Ogg1−/− mice

et al. 2005

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OGG1 (8-oxoguanine DNA glycosylase-1) is one of the main DNA glycosylases present in mammalian cells. The enzyme removes 7,8-dihydro-8-oxoguanine (8-oxoG) lesions, believed to be the most important oxidized lesions due to their relatively high incidence and their miscoding properties. This study shows that in prenatal mice brains the repair capacity for 8-oxoG is 5-10-fold higher than in adult mice brains. Western blot analysis and repair activity in extracts from Ogg1 À/À mice revealed that OGG1 was responsible for the efficient 8-oxoG removal from prenatal mice. To investigate how OGG1 protects against oxidative stress-induced mutagenesis, pregnant Big Blue/wild-type and Big Blue/Ogg1 À/À mice were exposed to nontoxic doses of gamma radiation. A 2.5-fold increase in the mutation frequency in Ogg1 À/À mouse brains was obtained by exposure to 3.5 Gy at day 19 postfertilization. This was largely due to GC to TA transversions, believed to originate from 8-oxoG mispairing with A during replication. Furthermore, rapid cell divisions seemed to be required for fixation of mutations, as a similar dose of radiation did not increase the mutation frequency, or the frequency of GC to TA transversion, in the adult brain.

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“…Although it is widely accepted that postmitotic cells and tissues have decreased DNA repair capacity (9), several findings indicate that postmitotic cells such as muscle cells and neurons express DNA glycosylases (56) and may up-regulate such expression in certain conditions. Thus, OGG1 activity in rat heart increases significantly with age (57).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Uracil-DNA Glycosylase Induces Neuronal Apoptosis

Kruman

Schwartz

Kruman

et al. 2004

Journal of Biological Chemistry

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A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result in a deficiency of DNA repair and increased DNA damage. Although indirect evidence suggests that DNA damage plays a role in neuronal apoptosis and in the pathogenesis of neurodegenerative disorders, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in neuronal survival. To test the hypothesis that repair of DNA damage associated with uracil misincorporation is critical for neuronal survival, we employed an antisense (AS) oligonucleotide directed against uracil-DNA glycosylase encoded by the UNG gene to deplete UNG in cultured rat hippocampal neurons. AS, but not a scrambled control oligonucleotide, induced apoptosis, which was associated with DNA damage analyzed by comet assay and up-regulation of p53. UNG mRNA and protein levels were decreased within 30 min and were undetectable within 6 -9 h of exposure to the UNG AS oligonucleotide. Whereas UNG expression is significantly higher in proliferating as compared with nonproliferating cells, such as neurons, the levels of UNG mRNA were increased in brains of cystathionine ␤-synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation of UNG expression.

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Base excision repair capacity in mitochondria and nuclei: tissue‐specific variations

Cited by 103 publications

References 34 publications

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

Repair and mutagenesis at oxidized DNA lesions in the developing brain of wild-type and Ogg1−/− mice

Suppression of Uracil-DNA Glycosylase Induces Neuronal Apoptosis

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