Repair of DNA damage in mitochondria

Sawyer, Dennis E.; Houten, Bennett Van

doi:10.1016/s0921-8777(99)00027-0

Cited by 131 publications

(66 citation statements)

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“…Although the precise molecular reason(s) that lead to the persistence of lesions in the mitochondrial genome is not clear, several explanations have been offered to clarify the increased vulnerability of the mtDNA to damage. These include the lack of a compact nucleosome structure as compared with the nDNA, the limited mitochondrial repair pathways, as well as the proximity of the mtDNA to the main source of ROS generation (9,23). More work is needed to understand the molecular events underlying the susceptibility of the mtDNA to oxidative damage.…”

mentioning

confidence: 99%

Cell Sorting Experiments Link Persistent Mitochondrial DNA Damage with Loss of Mitochondrial Membrane Potential and Apoptotic Cell Death

Santos¹,

Hunáková²,

Chen³

et al. 2003

Journal of Biological Chemistry

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193

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In order to understand the molecular events following oxidative stress, which lead to persistence of lesions in the mtDNA, experiments were performed on normal human fibroblast (NHF) expressing human telomerase reverse transcriptase (hTERT). The formation and repair of H 2 O 2 -induced DNA lesions were examined using quantitative PCR. It was found that NHF hTERTs show extensive mtDNA damage (ϳ4 lesions/10 kb) after exposure to 200 M H 2 O 2 , which is partially repaired during a recovery period of 6 h. At the same time, the nDNA seemed to be completely resistant to damage. Cell sorting experiments revealed persistent mtDNA damage at 24 h only in the fraction of cells with low mitochondrial membrane potential (⌬⌿m). Further analysis also showed increased production of H 2 O 2 by these cells, which subsequently undergo apoptosis. This work supports a hypothesis for a feed-forward cascade of reactive oxygen species generation and mtDNA damage and also suggested a possible mechanism for persistence of lesions in the mtDNA involving a drop in ⌬⌿m, compromised protein import, secondary reactive oxygen species generation, and loss of repair capacity.

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confidence: 99%

Cell Sorting Experiments Link Persistent Mitochondrial DNA Damage with Loss of Mitochondrial Membrane Potential and Apoptotic Cell Death

Santos¹,

Hunáková²,

Chen³

et al. 2003

Journal of Biological Chemistry

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193

163

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“…Work from our laboratory and that of others has established that repair of this damage is via a base excision repair (BER) pathway (13)(14)(15)(16). In support of this notion is the finding that mitochondria contain the basic enzymes required for BER (17,18), including the glycosylase/AP lyase OGG1, which is necessary for the initial steps in the removal of the mutagenic lesion 8-oxoguanine.…”

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confidence: 99%

Conditional Targeting of the DNA Repair Enzyme hOGG1 into Mitochondria

Rachek¹,

Grishko²,

Musiyenko³

et al. 2002

Journal of Biological Chemistry

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Oxidative damage to mitochondrial DNA (mtDNA) has been suggested to be a key factor in the etiologies of many diseases and in the normal process of aging. Although the presence of a repair system to remove this damage has been demonstrated, the mechanisms involved in this repair have not been well defined. In an effort to better understand the physiological role of recombinant 8-oxoguanine DNA glycosylase/apurinic lyase (OGG1) in mtDNA repair, we constructed an expression vector containing the gene for OGG1 downstream of the mitochondrial localization sequence from manganese-superoxide dismutase. This gene construct was placed under the control of a tetracycline-regulated promoter. Transfected cells that conditionally expressed OGG1 in the absence of the tetracycline analogue doxycycline and targeted this recombinant protein to mitochondria were generated. Western blots of mitochondrial extracts from vector-and OGG1-transfected clones with and without doxycycline revealed that removal of doxycycline for 4 days caused an approximate 8-fold increase in the amount of OGG1 protein in mitochondria. Enzyme activity assays and DNA repair studies showed that the doxycycline-dependent recombinant OGG1 is functional. Functional studies revealed that cells containing recombinant OGG1 were more proficient at repairing oxidative damage in their mtDNA, and this increased repair led to increased cellular survival following oxidative stress.

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“…However, subsequent studies have demonstrated that certain types of damage to DNA bases resulting from deamination, simple alkylation and oxidation can be efficiently repaired in mitochondria (reviewed in 29-31). Thus, the major DNA repair mechanism acting in mitochondria is base excision repair (BER) (29)(30)(31)(32)(33)(34). In general, BER starts with recognition and removal of a damaged or inappropriate base by a DNA glycosylase that cleaves the Nglycosylic bond between the base and the sugar.…”

Section: Mitochondrial Dna Damage and Repairmentioning

confidence: 99%

“…Mitochondrial BER has been demonstrated by numerous groups and shown to target oxidatively modified DNA bases, such as 8-oxoG and thymine glycol (29)(30)(31)(32)(33)(34)36,37). DNA repair enzymes isolated from mitochondria include several types of damage-specific DNA glycosylases (36)(37)(38)(39), AP endonuclease (40), and DNA ligase (41,42).…”

Section: Mitochondrial Dna Damage and Repairmentioning

confidence: 99%