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3. AGENTS THAT CAUSE DNA DAMAGE

Both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in many thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes.

http://meddev.uio.no/elaring/lcms13/ernaeringslaere/nutr-cancer-biology/illustrations/DNA-UV_damage_correct.jpg

Figure Intrastrand crosslink, one type of DNA lesion

DAMAGING AGENTS, INCLUDING ENDOGENOUS DAMAGE

Radiation

Ultraviolet light:

  • dimerises adjacent pyrimidines (intrastrand crosslinks)
  • also causes oxidative damage, depending on wavelength

Ionising radiation e.g. X-rays and gamma-rays: (Microwaves and radiowaves are non-ionising.)

  • strand breaks (single-stranded or double-stranded breaks)
  • base loss or AP sites (apurinic/apyrimidinic sites)
  • oxidation of bases
  • damage to deoxyribose
http://meddev.uio.no/elaring/lcms13/ernaeringslaere/nutr-cancer-biology/illustrations/Ionizing-radiation-symbol.jpg

Chemicals

Reactive oxygen (strand breaks, oxidised bases)

Alkylating agents (strand breaks, alkylated bases) formed from e.g. nitrosamines found in preserved meat and tobacco, see Food Toxicology lecture.

Cross-linking agents (intrastrand, interstrand, DNA-protein) e.g. psoralens, may lead to replication arrest and cell death

Agents that add ‘bulky adducts’ to the DNA e.g. aflatoxin and heterocyclic amines

Endogenous DNA damage

Alkylation; S-adenosyl methionine is the methyl donor in many metabolic reactions. Occasionally it might alkylate the wrong site. Alkylated bases in DNA such as 06-methylguanine or N-7-methyladenine are potentially mutagenic.

Oxidative stress is modulated by many factors:

  • Diet; antioxidants such as vitamin C and carotenoids decrease DNA oxidation. (See Antioxidant intervention trial in the Other Micronutrients e-lecture.)
  • Exercise; an acute burst of exercise can lead to oxidative damage.
  • Disease; diabetes, rheumatoid diseases and others are associated with oxidative stress, and DNA oxidation is also increased, see figure.

Infection, inflammation; the inflammatory response of macrophages involves release of reactive oxygen. There is evidence that tumours can arise at sites of previous inflammation, possibly as a result of the oxidation of DNA.

http://meddev.uio.no/elaring/lcms13/ernaeringslaere/nutr-cancer-biology/illustrations/dnadamageinhumandisease.JPG

Figure DNA breaks and oxidised bases in lymphocyte DNA were measured using the comet assay, in combination with endonuclease III (an enzyme that converts oxidised pyrimidines to breaks) and FPG (which converts oxidised purines to breaks). Both strand breaks and oxidised bases were elevated in lymphocytes of patients with the inflammatory rheumatoid disease ankylosing spondylitis, and in patients with insulin-dependent diabetes mellitus compared to normal persons.
(Ankylosing spondylitis: inflammation of the spine leading to stiffness and pain)

Free radicals and ROS

Oxidation damage arises from attack by reactive oxygen species (ROS).

See previous e-lecture Oxidative stress and vitamin E:

See Free radicals and ROS

Free radicals (or simply radicals) are defined as atoms or molecules with an unpaired electron, which makes them particularly reactive in redox reactions. The hydroxyl radical and superoxide are important examples. ROS include these free radicals, but also some potent oxidizing agents that are not radicals, such as hydrogen peroxide.

Reactive oxygen species:

  • Hydroxyl radical, •OH
  • Superoxide radical, •O2-
  • Peroxyl radicals ROO•
  • Hydrogen peroxide, H2O2
  • Singlet oxygen, 1O2
  • Hypochlorous acid, HOCl
http://meddev.uio.no/elaring/lcms13/ernaeringslaere/nutr-cancer-biology/illustrations/Small_table_radicals_non-radicals.jpg