Mutagenesis
A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code.
Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.
[1] DNA may be modified, either naturally or artificially, by a number of physical, chemical and biological agents, resulting in mutations.
Hermann Muller found that "high temperatures" have the ability to mutate genes in the early 1920s,[2] and in 1927, demonstrated a causal link to mutation upon experimenting with an x-ray machine, noting phylogenetic changes when irradiating fruit flies with relatively high dose of X-rays.
[3][4] Muller observed a number of chromosome rearrangements in his experiments, and suggested mutation as a cause of cancer.
[7] Lewis Stadler, Muller's contemporary, also showed the effect of X-rays on mutations in barley in 1928, and of ultraviolet (UV) radiation on maize in 1936.
[13] The metabolic process was identified in 1960s as catalysis by cytochrome P450, which produces reactive species that can interact with the DNA to form adducts, or product molecules resulting from the reaction of DNA and, in this case, cytochrome P450;[14][15] the mechanism by which the PAH adducts give rise to mutation, however, is still under investigation.
Mutation is also a major source for acquisition of resistance to antibiotics in bacteria, and to antifungal agents in yeasts and molds.
Metals such as cadmium, chromium, and nickel can increase mutagenesis in a number of ways in addition to direct DNA damage, for example reducing the ability to repair errors, as well as producing epigenetic changes.
In mammalian cells, stalling of replication at damaged sites induces a number of rescue mechanisms that help bypass DNA lesions, however, this may also result in errors.
Under physiological conditions the glycosidic bond may be hydrolyzed spontaneously and 10,000 purine sites in DNA are estimated to be depurinated each day in a cell.
In DNA replication, tautomerization alters the base-pairing sites and can cause the improper pairing of nucleic acid bases.
Many compounds, such as PAHs, aromatic amines, aflatoxin and pyrrolizidine alkaloids, may form reactive oxygen species catalyzed by cytochrome P450.
Some naturally occurring chemicals may also promote crosslinking, such as psoralens after activation by UV radiation, and nitrous acid.
Some crosslinkers such as cyclophosphamide, mitomycin C and cisplatin are used as anticancer chemotherapeutic because of their high degree of toxicity to proliferating cells.
[33] In human skin cells, thousands of dimers may be formed in a day due to normal exposure to sunlight.
Clinically, whether a tumor has formed as a direct consequence of UV radiation is discernible via DNA sequencing analysis for the characteristic context-specific dimerization pattern that occurs due to excessive exposure to sunlight.
Also, the intercalation into DNA of anthracyclines such as daunorubicin and doxorubicin interferes with the functioning of the enzyme topoisomerase II, blocking replication as well as causing mitotic homologous recombination.
For instance, in bacteria, while modulation of the SOS response and endogenous prophage DNA synthesis has been shown to increase Acinetobacter baumannii resistance to ciprofloxacin.
[16] Resistance mechanisms are presumed to be linked to chromosomal mutation untransferable via horizontal gene transfer in some members of family Enterobacteriaceae, such as E. coli, Salmonella spp., Klebsiella spp., and Enterobacter spp.
[21][39][40] In the laboratory, mutagenesis is a technique by which DNA mutations are deliberately engineered to produce mutant genes, proteins, or strains of organisms.
The mutation may also produce mutant proteins with altered properties, or enhanced or novel functions that may prove to be of use commercially.
Mutant strains of organisms that have practical applications, or allow the molecular basis of particular cell function to be investigated, may also be produced.
