Oxidative DNA Damage(ODD)

Oxidative DNA Damage (ODD)

Oxidative DNA damage (ODD) refers to the alterations in DNA structure caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). These highly reactive molecules can lead to various types of DNA lesions, which, if not repaired, may result in mutations, genomic instability, and contribute to the development of various diseases, including blood cancer and solid organ cancer.

Mechanisms of Oxidative DNA Damage

1. Formation of Lesions: The most common oxidative DNA lesion is 8-oxo-2′-deoxyguanosine (8-oxo-dG), which occurs when guanine is oxidized. This modification can mispair during DNA replication, leading to G:C to T:A transversions. Other notable lesions include 8-oxo-dA and various abasic sites resulting from the loss of bases.
2. Sources of ROS: Oxidative stress can originate from endogenous sources (such as metabolic processes) or exogenous factors (like ionizing radiation, UV light, and environmental toxins). Each day, human cells are estimated to experience hundreds to thousands of oxidative modifications.

Repair Mechanisms

Cells have evolved several pathways to repair oxidative DNA damage:

• Base Excision Repair (BER): This is the primary mechanism for repairing small base lesions. It involves the recognition and excision of damaged bases by specific glycosylases (e.g., OGG1 for 8-oxo-dG), followed by the removal of the resultant abasic site and replacement with an undamaged nucleotide.
• Nucleotide Excision Repair (NER): This pathway is responsible for repairing bulky lesions that distort the DNA helix and can also address some oxidative damage.
• Mismatch Repair (MMR): While primarily involved in correcting replication errors, MMR can also play a role in repairing certain types of oxidative damage.

Biological Consequences

1. Mutagenesis: If oxidative damage is not properly repaired, it can lead to mutations that contribute to blood cancer and solid organ cancer development. For instance, persistent accumulation of 8-oxo-dG in critical genes may disrupt normal cellular functions.
2. Genomic Instability: Accumulation of unrepaired lesions can lead to double-strand breaks and chromosomal rearrangements, further promoting genomic instability.
3. Disease Associations: Elevated levels of oxidative DNA damage have been linked to various diseases, including blood cancer and solid organ cancer, neurodegenerative disorders (like Alzheimer’s disease), and aging-related conditions.

Measurement and Detection

Detecting oxidative DNA damage is crucial for understanding its implications in health and disease:

• Biomarkers: Commonly used biomarkers for oxidative DNA damage include 8-oxo-dG levels in urine or blood samples. Advanced techniques such as high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) are employed for accurate quantification.
• Research and Clinical Trials Applications: Studies investigating oxidative stress often measure both the levels of oxidized bases and the efficiency of repair mechanisms to assess cellular responses to environmental stressors.

Conclusion

Oxidative DNA damage represents a significant threat to genomic integrity. Understanding its mechanisms, repair pathways, and implications for health is critical for developing strategies to mitigate its effects, particularly in the context of aging and disease prevention.

References

1. Genome Biology. (2018). Genomic landscape of oxidative DNA damage and repair reveals… Retrieved from Genome Biology
2. PubMed. (2004). Oxidative DNA damage: mechanisms, mutation, and disease. Retrieved from PubMed
3. Wikipedia. (2024). DNA oxidation. Retrieved from Wikipedia
4. PubMed Central. (2017). Oxidative DNA Damage & Repair: An Introduction. Retrieved from PMC
5. MDPI Antioxidants Journal. (2023). Oxidative DNA Damage and Repair: Mechanisms, Mutations, and Relation to Diseases. Retrieved from MDPI