The discovery of a new family of mammalian enzymes for repair of oxidatively damaged DNA, and its physiological implications

Hazra, Tapas K.

doi:10.1093/carcin/24.2.155

Cited by 65 publications

(32 citation statements)

References 28 publications

(34 reference statements)

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“…proteins with exposed thiol groups) (56,57). In addition, reduction of Lon may lead to higher levels of repair proteins such as OGG1, NTH1, and NEIL1 (58,59). We do not know whether mtDNA binding by Lon functions independently of its ATPase and/or protease activity.…”

Section: Discussionmentioning

confidence: 99%

Roles for the Human ATP-dependent Lon Protease in Mitochondrial DNA Maintenance

Lü

Yadav

Shah

et al. 2007

Journal of Biological Chemistry

134

121

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Human mitochondrial Lon is an ATP-powered proteolytic machine that specifically binds to single-stranded G-rich DNA and RNA in vitro. However, it is unknown whether Lon binds mitochondrial DNA (mtDNA) in living cells or functions in mtDNA integrity. Here, we demonstrate that Lon interacts with the mitochondrial genome in cultured cells using mtDNA immunoprecipitation (mIP). Lon associates with sites distributed primarily within one-half of the genome and preferentially with the control region for mtDNA replication and transcription. Bioinformatic analysis of mIP data revealed a G-rich consensus sequence. Consistent with these findings, in vitro experiments showed that the affinity of Lon for single-stranded DNA oligonucleotides correlates with conformity to this consensus. To examine the role of Lon in mtDNA maintenance, cells carrying an inducible short hairpin RNA for Lon depletion were used. In control and Lon-depleted cells, mtDNA copy number was essentially the same in the presence or absence of oxidative stress. However when oxidatively stressed, control cells exhibited an increased frequency of mtDNA lesions, whereas Lon-depleted cells showed little if any mtDNA damage. This suggests that oxidative mtDNA damage is permitted when Lon is present and prevented when Lon is substantially depleted. Upon oxidative stress, mIP showed reduced Lon binding to mtDNA; however binding to the control region was unaffected. It is unlikely that oxidative modification of Lon blocks its ability to bind DNA in vivo as results show that oxidized purified Lon retains sequence-specific DNA binding. Taken together, these results demonstrate that mtDNA binding is a physiological function of Lon and that cellular levels of Lon influence sensitivity to mtDNA damage. These findings suggest roles for Lon in linking protein and mtDNA quality control.

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Section: Discussionmentioning

confidence: 99%

Roles for the Human ATP-dependent Lon Protease in Mitochondrial DNA Maintenance

Lü

Yadav

Shah

et al. 2007

Journal of Biological Chemistry

134

121

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“…Candidates include the recently characterized homologue of the bacterial Fpg/Nei DNA glycosylase, Neil 1, which shares with OGG1 the ability to remove 8-oxoG from 8-oxoG:C bp (14). In addition, DNA mismatch repair is known to play a role in reducing the burden of DNA 8-oxoG and associated mutations (15,16).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of the Oxidative Base Lesion 8-Hydroxyguanine in DNA of Tumor-Prone Mice Defective in Both the Myh and Ogg1 DNA Glycosylases

et al. 2004

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The OGG1 and MYH DNA glycosylases prevent the accumulation of DNA 8-hydroxyguanine. In Myh ؊/؊ mice, there was no time-dependent accumulation of DNA 8-hydroxyguanine in brain, small intestine, lung, spleen, or kidney. Liver was an exception to this general pattern. Inactivation of both MYH and OGG1 caused an age-associated accumulation of DNA 8-hydroxyguanine in lung and small intestine. The effects of abrogated OGG1 and MYH on hepatic DNA 8-hydroxyguanine levels were additive. Because there is an increased incidence of lung and small intestine cancer in Myh ؊/؊ /Ogg1 ؊/؊ mice, these findings support a causal role for unrepaired oxidized DNA bases in cancer development.

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“…These so-called Nei-like or NEIL enzymes belong to a new glycosylase superfamily for the repair of oxidative damage, defined by the Fpg/MutM enzyme of E. coli and its paralogue, Nei, also called endonuclease VIII (for recent reviews, see 59,146). NEIL1 (9,61,100,139) and NEIL2 (58) have overlapping specificity with both NTH and OGG1, acting on 8-oxoG as well as oxidized pyrimidines, although published reports of their precise substrate specificity and expression patterns are somewhat contradictory (146).…”

Section: Barnes Lindahlmentioning

confidence: 99%

Repair and Genetic Consequences of Endogenous DNA Base Damage in Mammalian Cells

2004

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Key Words DNA repair, mutagenesis, knock-out mice, uracil in DNA, DNA oxidation ■ Abstract Living organisms dependent on water and oxygen for their existence face the major challenge of faithfully maintaining their genetic material under a constant attack from spontaneous hydrolysis and active oxygen species and from other intracellular metabolites that can modify DNA bases. Repair of endogenous DNA base damage by the ubiquitous base-excision repair pathway largely accounts for the significant turnover of DNA even in nonreplicating cells, and must be sufficiently accurate and efficient to preserve genome stability compatible with long-term cellular viability.

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The discovery of a new family of mammalian enzymes for repair of oxidatively damaged DNA, and its physiological implications

Cited by 65 publications

References 28 publications

Roles for the Human ATP-dependent Lon Protease in Mitochondrial DNA Maintenance

Roles for the Human ATP-dependent Lon Protease in Mitochondrial DNA Maintenance

Accumulation of the Oxidative Base Lesion 8-Hydroxyguanine in DNA of Tumor-Prone Mice Defective in Both the Myh and Ogg1 DNA Glycosylases

Repair and Genetic Consequences of Endogenous DNA Base Damage in Mammalian Cells

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