Mutagens
Mutagens are chemical or physical agents that increase the occurrence of mutations. Biological agents, such as certain viruses or transposable genetic elements, can also increase the frequency of mutations and thus act as mutagens.
Physical Mutagens
Physical mutagens include ionizing (e.g., X-ray, B-ray) and non-ionizing (e.g., UV-ray) radiations. H. J. Muller first demonstrated that X-rays can cause mutations. He found that X-ray treatment markedly increased the frequency of sex-linked recessive lethal mutations in Drosophila melanogaster.
Effects of Radiation on DNA
The effects of radiation on DNA may be direct or indirect. Direct effects result from the direct interaction of the radiations with DNA. Indirect effects result from the interaction of DNA with reactive species generated by the radiation. The extent of direct and indirect effects of radiations on DNA depends on the type of radiation and its intensity.
Ionizing Radiation
Ionizing radiation mainly causes strand breakage by directly interacting with DNA, acting as a clastogenic agent that causes chromosomal breakage. Ionizing radiation may act indirectly by stimulating the formation of reactive species such as hydroxyl radicals in the cell. Due to the aqueous nature of biological systems, many different types of reactive oxygen species are generated by the effects of ionizing radiation on water. These species can damage bases and cause different adducts and degradation products.
Non-Ionizing Radiation (UV Radiation)
Non-ionizing radiations, such as UV radiation, also act as potent physical mutagens and generate a number of photoproducts in DNA. The UV radiation spectrum has been subdivided into three wavelength bands: UV-A (400 to 320 nm), UV-B (320 to 280 nm), and UV-C (280 to 100 nm). UV radiation at 260 nm, which corresponds to the DNA absorption peak, induces dimer formation of adjacent pyrimidine bases, especially when both are thymines.
Pyrimidine Dimers
Adjacent pyrimidines become covalently linked by the formation of a four-membered cyclobutane ring structure resulting from the saturation of their respective 5,6 double bonds. This structure, formed by photochemical cycloaddition, is referred to as a cyclobutane pyrimidine dimer. Thymine dimer is the most common form of pyrimidine dimer, though other pyrimidine combinations also form dimers.
UV-Induced Pyrimidine Dimerization
The second type of UV-induced pyrimidine dimer is the pyrimidine (6-4) pyrimidone photoproduct, in which carbon numbers 4 and 6 of adjacent pyrimidines become covalently linked. UV-induced dimerization usually results in a deletion mutation when the modified strand is copied.
Cytosine Hydrate Formation
Ultraviolet irradiation of DNA also produces cytosine hydrate, which is the addition of a water molecule across the 5,6 double bond to form a hydroxy derivative.
Heat-Induced DNA Damage
Heat stimulates the water-induced cleavage of the N-glycosidic bond that attaches the base to the sugar component of the nucleotide. This occurs more frequently with purines than with pyrimidines and results in an AP (apurinic/apyrimidinic) site. The sugar-phosphate left behind is unstable and rapidly degrades, leaving a gap if the DNA molecule is double-stranded. This reaction is not normally mutagenic because cells have effective systems for repairing nicks.
