DNA oxidation

Detailed article on DNA oxidation

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DNA oxidation refers to the process by which reactive oxygen species (ROS) interact with DNA molecules, leading to structural modifications that can affect the integrity and function of the genetic material. This process is a significant aspect of cellular metabolism and has implications for aging, cancer, and various diseases.

Overview

DNA oxidation is primarily caused by reactive oxygen species, which are byproducts of normal cellular metabolism, particularly in the mitochondria. These species include superoxide anions (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (•OH). When these ROS interact with DNA, they can cause a variety of lesions, including single and double-strand breaks, base modifications, and cross-linking.

Mechanisms of DNA Oxidation

The most common oxidative DNA lesion is 8-oxo-2'-deoxyguanosine (8-oxo-dG), which results from the oxidation of guanine. This lesion can mispair with adenine during DNA replication, leading to G:C to T:A transversions, a type of point mutation. Other oxidative lesions include thymine glycol, 5-hydroxycytosine, and 5-hydroxyuracil.

Sources of Reactive Oxygen Species

• Mitochondrial respiration: The electron transport chain in mitochondria is a major source of ROS.
• Inflammation: Activated immune cells produce ROS as part of the defense mechanism against pathogens.
• Environmental factors: UV radiation, pollution, and smoking can increase ROS levels.

Biological Consequences

DNA oxidation can lead to mutations, which may result in cancer if they occur in oncogenes or tumor suppressor genes. Additionally, oxidative DNA damage is implicated in aging and neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

DNA Repair Mechanisms

Cells have evolved several repair mechanisms to counteract DNA oxidation:

• Base excision repair (BER): This pathway is primarily responsible for repairing small, non-helix-distorting base lesions, such as 8-oxo-dG.
• Nucleotide excision repair (NER): This pathway repairs bulky, helix-distorting lesions.
• Mismatch repair (MMR): This system corrects base mispairings that escape proofreading during DNA replication.

Research and Clinical Implications

Understanding DNA oxidation is crucial for developing therapeutic strategies to prevent and treat diseases associated with oxidative stress. Antioxidants, which neutralize ROS, are being studied for their potential to reduce oxidative DNA damage.

Also see

• Reactive oxygen species
• Base excision repair
• Oxidative stress
• 8-oxo-2'-deoxyguanosine
• Cancer biology

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  Guanine and 2 oxidative products
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  Colonic epithelium mouse without tumorigenesis (A) and with tumorigenesis (B). Brown shows 8-oxo-dG
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  Initiation of DNA demethylation at a CpG site
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  Demethylation of 5-methylcytosine