Compromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases.

2.50
Hdl Handle:
http://hdl.handle.net/10541/82317
Title:
Compromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases.
Authors:
Karahalil, Bensu; De Souza-Pinto, Nadja C; Parsons, Jason L; Elder, Rhoderick H; Bohr, Vilhelm A
Abstract:
Mitochondrial DNA is constantly exposed to high levels of endogenously produced reactive oxygen species, resulting in elevated levels of oxidative damaged DNA bases. A large spectrum of DNA base alterations can be detected after oxidative stress, and many of these are highly mutagenic. Thus, an efficient repair of these is necessary for survival. Some of the DNA repair pathways involved have been characterized, but others are not yet determined. A DNA repair activity for thymine glycol and other oxidized pyrimidines has been described in mammalian mitochondria, but the nature of the glycosylases involved in this pathway remains unclear. The generation of mouse strains lacking murine thymine glycol-DNA glycosylase (mNTH1) and/or murine 8-oxoguanine-DNA glycosylase (mOGG1), the two major DNA N-glycosylase/apurinic/apyrimidinic (AP) lyases involved in the repair of oxidative base damage in the nucleus, has provided very useful biological model systems for the study of the function of these and other glycosylases in mitochondrial DNA repair. In this study, mouse liver mitochondrial extracts were generated from mNTH1-, mOGG1-, and [mNTH1, mOGG1]-deficient mice to ascertain the role of each of these glycosylases in the repair of oxidized pyrimidine base damage. We also characterized for the first time the incision of various modified bases in mitochondrial extracts from a double-knock-out [mNTH1, mOGG1]-deficient mouse. We show that mNTH1 is responsible for the repair of thymine glycols in mitochondrial DNA, whereas other glycosylase/AP lyases also participate in removing other oxidized pyrimidines, such as 5-hydroxycytosine and 5-hydroxyuracil. We did not detect a backup glycosylase or glycosylase/AP lyase activity for thymine glycol in the mitochondrial mouse extracts.
Affiliation:
Laboratory of Molecular Gerontology, National Institute on Aging,, National Institutes of Health, Baltimore, Maryland 21224, USA.
Citation:
Compromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases. 2003, 278 (36):33701-7 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
5-Sep-2003
URI:
http://hdl.handle.net/10541/82317
DOI:
10.1074/jbc.M301617200
PubMed ID:
12819227
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorKarahalil, Bensu-
dc.contributor.authorDe Souza-Pinto, Nadja C-
dc.contributor.authorParsons, Jason L-
dc.contributor.authorElder, Rhoderick H-
dc.contributor.authorBohr, Vilhelm A-
dc.date.accessioned2009-09-23T11:52:01Z-
dc.date.available2009-09-23T11:52:01Z-
dc.date.issued2003-09-05-
dc.identifier.citationCompromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases. 2003, 278 (36):33701-7 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid12819227-
dc.identifier.doi10.1074/jbc.M301617200-
dc.identifier.urihttp://hdl.handle.net/10541/82317-
dc.description.abstractMitochondrial DNA is constantly exposed to high levels of endogenously produced reactive oxygen species, resulting in elevated levels of oxidative damaged DNA bases. A large spectrum of DNA base alterations can be detected after oxidative stress, and many of these are highly mutagenic. Thus, an efficient repair of these is necessary for survival. Some of the DNA repair pathways involved have been characterized, but others are not yet determined. A DNA repair activity for thymine glycol and other oxidized pyrimidines has been described in mammalian mitochondria, but the nature of the glycosylases involved in this pathway remains unclear. The generation of mouse strains lacking murine thymine glycol-DNA glycosylase (mNTH1) and/or murine 8-oxoguanine-DNA glycosylase (mOGG1), the two major DNA N-glycosylase/apurinic/apyrimidinic (AP) lyases involved in the repair of oxidative base damage in the nucleus, has provided very useful biological model systems for the study of the function of these and other glycosylases in mitochondrial DNA repair. In this study, mouse liver mitochondrial extracts were generated from mNTH1-, mOGG1-, and [mNTH1, mOGG1]-deficient mice to ascertain the role of each of these glycosylases in the repair of oxidized pyrimidine base damage. We also characterized for the first time the incision of various modified bases in mitochondrial extracts from a double-knock-out [mNTH1, mOGG1]-deficient mouse. We show that mNTH1 is responsible for the repair of thymine glycols in mitochondrial DNA, whereas other glycosylase/AP lyases also participate in removing other oxidized pyrimidines, such as 5-hydroxycytosine and 5-hydroxyuracil. We did not detect a backup glycosylase or glycosylase/AP lyase activity for thymine glycol in the mitochondrial mouse extracts.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshBase Sequence-
dc.subject.meshBlotting, Western-
dc.subject.meshBorohydrides-
dc.subject.meshCell Nucleus-
dc.subject.meshDNA Repair-
dc.subject.meshDNA-Formamidopyrimidine Glycosylase-
dc.subject.meshDeoxyribonuclease (Pyrimidine Dimer)-
dc.subject.meshElectrophoresis, Polyacrylamide Gel-
dc.subject.meshEndodeoxyribonucleases-
dc.subject.meshEscherichia coli Proteins-
dc.subject.meshLiver-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshMitochondria, Liver-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshN-Glycosyl Hydrolases-
dc.subject.meshOligonucleotides-
dc.subject.meshOxidative Stress-
dc.subject.meshOxygen-
dc.subject.meshPyrimidines-
dc.subject.meshReactive Oxygen Species-
dc.subject.meshUracil-
dc.titleCompromised incision of oxidized pyrimidines in liver mitochondria of mice deficient in NTH1 and OGG1 glycosylases.en
dc.typeArticleen
dc.contributor.departmentLaboratory of Molecular Gerontology, National Institute on Aging,, National Institutes of Health, Baltimore, Maryland 21224, USA.en
dc.identifier.journalThe Journal of Biological Chemistryen

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.