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essential nutrient 21 22 23 many chemical mutagens require biological activation to become mutagenic an important group of enzymes involved in the generation of mutagenic metabolites is cytochrome p450 24 other enzymes that may also produce mutagenic metabolites include glutathione s transferase and microsomal epoxide hydrolase mutagens that are not mutagenic by themselves but require biological activation are called promutagens while most mutagens produce effects that ultimately result in errors in replication for example creating adducts that interfere with replication some mutagens may directly affect the replication process or reduce its fidelity base analog such as 5 bromouracil may substitute for thymine in replication 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 25 mutations often arise as a result of problems caused by dna lesions during replication resulting in errors in replication in bacteria extensive damage to dna due to mutagens results in single stranded dna gaps during replication this induces the sos response an emergency repair process that is also error prone thereby generating mutations 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 the y family of dna polymerases specializes in dna lesion bypass in a process termed translesion synthesis tls whereby these lesion bypass polymerases replace the stalled high fidelity replicative dna polymerase transit the lesion and extend the dna until the lesion has been passed so that normal replication can resume these processes may be error prone or error free endogenous dna damage edit endogenous dna damage is caused by internal cellular processes rather than external agents cellular processes can generate reactive oxygen species that can modify the dna and dna can also undergo spontaneous hydrolysis while errors in replication can result in mutations citation needed dna damage and spontaneous mutation edit the number of dna damage episodes occurring in a mammalian cell per day is high more than 60 000 per day frequent occurrence of dna damage is likely a problem for all dna containing organisms and the need to cope with dna damage and minimize their deleterious effects is likely a fundamental problem for life 26 most spontaneous mutations likely arise from error prone trans lesion synthesis past a dna damage site in the template strand during dna replication this process can overcome potentially lethal blockages but at the cost of introducing inaccuracies in daughter dna the causal relationship of dna damage to spontaneous mutation is illustrated by aerobically growing e coli bacteria in which 89 of spontaneously occurring base substitution mutations are caused by dna damage induced by reactive oxygen species 27 in yeast more than 60 of spontaneous single base pair substitutions and deletions are likely caused by trans lesion synthesis 28 an additional significant source of mutations in eukaryotes is the inaccurate dna repair process non homologous end joining that is often employed in repair of double strand breaks 29 in general it appears that the main underlying cause of spontaneous mutation is error prone trans lesion synthesis during dna replication and that the error prone non homologous end joining repair pathway may also be an important contributor in eukaryotes reactive oxygen species and oxidative damages edit reactive oxygen species is the typical byproducts of the electron transport chain during cellular respiration 30 low levels of reactive oxygen species can function in cellular signaling and immune defenses but excessive levels of reactive oxygen species can damage bases and the sugar phosphate backbone of the dna 8 oxo guanine an oxidized formed of guanine mispair with adenine during replication instead of cytosine causing an g c to t a mutation if left unrepaired 30 spontaneous hydrolysis edit base deamination edit base deamination is a major source of spontaneous mutagenesis happening in the human cells and it is the loss of amine groups from a dna base such as cytosine c adenine a guanine g and 5 methylcytosine it changes the base pairing behavior so that cytosine c becomes uracil u adenine a becomes hypoxanthine guanine g becomes xanthine and 5 methylcytosine becomes thymine t 30 cytosine and 5 methylcytosine deamination is the most frequently deaminated dna bases with 5 methylcytosine being three to four times more deaminated than cytosine for cytosine deamination in dna cytosine c is usually paired with guanine g but after the deamination has happened it creates a uracil u and guanine g mismatch and if the mismatch is not properly repaired uracil can pair with adenine creating a c g to t a mutation while the deamination of 5 methylcytosine generates thymine t instead of uracil u creating a g t mismatch 30 depurination edit dna is not entirely stable in aqueous solution and depurination of the dna can occur under physiological conditions the glycosidic bond may be hydrolyzed spontaneously and 5000 purine sites in dna are estimated to be depurinated each day in a cell 20 31 numerous dna repair pathways exist for dna however if the apurinic site is not repaired misincorporation of nucleotides may occur during replication adenine is preferentially incorporated by dna polymerases in an apurinic site 32 tautomerism edit main article tautomer tautomerization is the process by which compounds spontaneously rearrange themselves to assume their structural isomer forms for example the keto c o forms of guanine and thymine can rearrange into their rare enol oh forms while the amino nh 2 forms of adenine and cytosine can result in the rarer imino nh forms in dna replication tautomerization alters the base pairing sites and can cause the improper pairing of nucleic acid bases 33 modification of bases edit bases may be modified endogenously by normal cellular molecules for example dna may be methylated by s adenosylmethionine thus altering the expression of the marked gene without incurring a mutation to the dna sequence itself histone modification is a related process in which the histone proteins around which dna coils can be similarly modified via methylation phosphorylation or acetylation these modifications may act to alter gene expression of the local dna and may also act to denote locations of damaged dna in need of repair dna may also be glycosylated by reducing sugars citation needed many compounds such as pahs aromatic amines aflatoxin and pyrrolizidine alkaloids may form reactive oxygen species catalyzed by cytochrome p450 these metabolites form adducts with the dna which can cause errors in replication and the bulky aromatic adducts may form stable intercalation between bases and block replication the adducts may also induce conformational changes in the dna some adducts may also result in the depurination of the dna 34 it is however uncertain how significant such depurination as caused by the adducts is in generating mutation alkylation and arylation of bases can cause errors in replication some alkylating agents such as n nitrosamines may require the catalytic reaction of cytochrome p450 for the formation of a reactive alkyl cation n 7 and o 6 of guanine and the n 3 and n 7 of adenine are most susceptible to attack n 7 guanine adducts form the bulk of dna adducts but they appear to be non mutagenic alkylation at o 6 of guanine however is harmful because excision repair of o 6 adduct of guanine may be poor in some tissues such as the brain 35 the o 6 methylation of guanine can result in g to a transition while o 4 methylthymine can be mispaired with guanine the type of the mutation generated however may be dependent on the size and type of the adduct as well as the dna sequence 36 ionizing radiation and reactive oxygen species often oxidize guanine to produce 8 oxoguanine citation needed see also epigenetics exogenous dna damage edit arrows indicates chromosomal breakages due to dna damage exogenous dna damage is structural alteration of dna caused by external environmental agents including uv radiation ionizing radiation and chemical toxins citation needed backbone damage edit ionizing radiation may produce highly reactive free radicals that can break the bonds in the dna double stranded breakages are especially damaging and hard to repair producing translocation and deletion of part of a chromosome alkylating agents like mustard gas diet tobacco smoke may also cause breakages in the dna backbone endogenous processes may also such as oxidative stress may also generate highly reactive oxygen species that can damage the dna citation needed crosslinking edit main article crosslinking of dna covalent bonds between the bases of nucleotides in dna be they in the same strand or opposing strands is referred to as crosslinking of dna crosslinking of dna may affect both the replication and the transcription of dna and it may be caused by exposure to a variety of agents some naturally occurring chemicals may also promote crosslinking such as psoralens after activation by uv radiation and nitrous acid interstrand cross linking between two strands causes more damage as it blocks replication and transcription and can cause chromosomal breakages and rearrangements some crosslinkers such as cyclophosphamide mitomycin c and cisplatin are used as anticancer chemotherapeutic because of their high degree of toxicity to proliferating cells citation needed dimerization edit main article dimer dimerization consists of the bonding of two monomers to form an oligomer such as the formation of pyrimidine dimers as a result of exposure to uv radiation which promotes the formation of a cyclobutyl ring between adjacent thymines in dna 37 these bulky bases would cause a distortion in the dna helixes and can interfere with dna replication and transcription in human skin cells thousands of dimers may be formed in a day due to normal exposure to sunlight dna polymerase η may help bypass these lesions in an error free manner 38 however individuals with defective dna repair function such as those with xeroderma pigmentosum are sensitive to sunlight and may be prone to skin cancer ethidium intercalated between two adenine thymine base pairs 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 39 intercalation between bases edit main article intercalation biochemistry the planar structure of chemicals such as ethidium bromide and proflavine allows them to insert between bases in dna this insert causes the dna s backbone to stretch and makes slippage in dna during replication more likely to occur since the bonding between the strands is made less stable by the stretching forward slippage will result in deletion mutation while reverse slippage will result in an insertion mutation 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 citation needed insertional mutagenesis edit main article insertional mutagenesis transposons and viruses or retrotransposons may insert dna sequences into coding regions or functional elements of a gene and result in inactivation of the gene 40 dna repair pathway edit dna damage happens frequently but dna damage does not always become a mutation only after the repair mechanism has failed or inaccurate allowing the damages to bypass then the mutation would happen and potentially lead to diseases like cancer citation needed base excision repair edit base excision repair corrects the small non helix distorting lesions of dna helix such as oxidative deaminated alkylation as well as basic single abase damages 30 dna glycosylase within the base excision repair mechanism recognizes those damages and cleaves the n glycosidic bond leave behind an abasic sites dna backbone would then be cut at that site by ap endonuclease after that dna polymerase fills the gap nucleotide excision repair edit nucleotide excision repair removes bulky lesion such as cpds clarification needed and 6 4 pp from uv radiation or damage from chemotherapeutic agents there are two major branches of nucleotide excision repair globular genome nucleotide excision repair and transcription coupled nucleotide excision repair globular genome ner the xpc rad23b and cetn2 protein complex scans for whole genome damage once the damage is found endonuclease such as xpf ercc1 and xpg will cut out the lesion from 5 to 3 and pol ε or xrcc1 lig3 will carry out the gap filling synthesis and ligation 30 mismatch repair edit mismatch repair removes base mismatch that have arisen during replication and the insertion deletion loop 41 humans employ the mutsα heterodimer msh2 msh6 to recognize the base mismatch 42 once the mismatch is found exo1 carries out the 5 directed mismatch excision which creates a gap later being filled by polδ rfc and hmgb 43 adaptive mutagenesis mechanisms edit main article adaptive mutation adaptive mutagenesis has been defined as mutagenesis mechanisms that enable an organism to adapt to an environmental stress since the variety of environmental stresses is very broad the mechanisms that enable it are also quite broad as far as research on the field has shown 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 44 chromosomal events specially gene amplification seem also to be relevant to this adaptive mutagenesis in bacteria 45 research in eukaryotic cells is much scarcer but chromosomal events seem also to be rather relevant while an ectopic intrachromosomal recombination has been reported to be involved in acquisition of resistance to 5 fluorocytosine in saccharomyces cerevisiae 17 genome duplications have been found to confer resistance in s cerevisiae to nutrient poor environments 21 46 47 laboratory applications edit main article mutagenesis molecular biology technique in the laboratory mutagenesis is a technique by which dna mutations are deliberately engineered to produce mutant genes proteins or strains of organisms various constituents of a gene such as its control elements and its gene product may be mutated so that the function of a gene or protein can be examined in detail the mutation may a...