Compromised Incision of Oxidized Pyrimidines in Liver Mitochondria of Mice Deficient in NTH1 and OGG1 Glycosylases

Bensu Karahalil, Nadja C. De Souza-Pinto, Jason L. Parsons, Rhoderick H. Elder, Vilhelm A. Bohr

    Research output: Contribution to journalArticlepeer-review

    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.
    Original languageEnglish
    Pages (from-to)33701-33707
    Number of pages6
    JournalJournal of Biological Chemistry
    Volume278
    Issue number36
    DOIs
    Publication statusPublished - 5 Sept 2003

    Keywords

    • Animals
    • Base Sequence
    • Blotting, Western
    • pharmacology: Borohydrides
    • metabolism: Cell Nucleus
    • DNA Repair
    • DNA-Formamidopyrimidine Glycosylase
    • Deoxyribonuclease (Pyrimidine Dimer)
    • Electrophoresis, Polyacrylamide Gel
    • genetics: Endodeoxyribonucleases
    • Escherichia coli Proteins
    • metabolism: Liver
    • Mice
    • Mice, Knockout
    • metabolism: Mitochondria, Liver
    • Molecular Sequence Data
    • genetics: N-Glycosyl Hydrolases
    • chemistry: Oligonucleotides
    • Oxidative Stress
    • metabolism: Oxygen
    • chemistry: Pyrimidines
    • Reactive Oxygen Species
    • chemistry: Uracil

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