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Oxidative DNA damage processing and changes with aging
1Laboratory of Molecular Genetics, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Abstract:
Living organisms are constantly exposed to oxidative stress from environmental agents and from endogenous metabolic processes. The resulting oxidative modifications occur in proteins, lipids and DNA. Since proteins and lipids are readily degraded and resynthesized, the most significant consequence of the oxidative stress is thought to be the DNA modifications, which can become permanent via the formation of mutations and other types of genomic instability. Many different DNA base changes have been seen following some form of oxidative stress, and these lesions are widely considered as instigators for the development of cancer and are also implicated in the process of aging. Several studies have documented that oxidative DNA lesions accumulate with aging, and it appears that the major site of this accumulation is mitochondrial DNA rather than nuclear DNA. The DNA repair mechanisms involved in the removal of oxidative DNA lesions are much more complex than previously considered. They involve base excision repair (BER) pathways and nucleotide excision repair (NER) pathways, and there is currently a great deal of interest in clarification of the pathways and their interactions. We have used a number of different approaches to explore the mechanism of the repair processes, and we are able to examine the repair of different types of lesions and to measure different steps of the repair processes. Furthermore, we can measure the DNA damage processing in the nuclear DNA and separately, in the mitochondrial DNA. Contrary to widely held notions, mitochondria have efficient DNA repair of oxidative DNA damage and we are exploring the mechanisms. In a human disorder, Cockayne syndrome (CS), characterized by premature aging, there appear to be deficiencies in the repair of oxidative DNA damage in the nuclear DNA, and this may be the major underlying cause of the disease.
Insights
Oxidative stress damages DNA, leading to aging and cancer. Organisms possess DNA repair mechanisms, but deficiencies in nuclear DNA repair, as seen in Cockayne syndrome, may cause premature aging.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Organisms face constant oxidative stress from internal and external sources.
- Oxidative stress causes modifications in proteins, lipids, and DNA, with DNA damage being a primary concern due to its link to mutations, cancer, and aging.
- Oxidative DNA lesions accumulate with age, predominantly in mitochondrial DNA.
Purpose of the Study:
- To investigate the complex DNA repair mechanisms for oxidative damage.
- To differentiate and measure DNA repair processes in both nuclear and mitochondrial DNA.
- To explore the role of DNA repair deficiencies in premature aging disorders like Cockayne syndrome.
Main Methods:
- Utilized diverse experimental approaches to study DNA repair pathways.
- Examined the repair of various oxidative DNA lesions.
- Quantified different stages of DNA repair processes.
- Measured DNA damage processing distinctly in nuclear and mitochondrial DNA.
Main Results:
- Mitochondria possess efficient DNA repair mechanisms for oxidative damage, challenging previous assumptions.
- Identified potential deficiencies in nuclear DNA repair of oxidative damage in Cockayne syndrome.
- Linked these repair deficiencies to the premature aging phenotype observed in Cockayne syndrome.
Conclusions:
- Mitochondrial DNA repair is more robust than previously thought.
- Deficiencies in nuclear DNA repair of oxidative stress are implicated in premature aging disorders.
- Further research into DNA repair pathways is crucial for understanding aging and disease.