Biology:Mutagenesis

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Mutagenesis (/mjuːtəˈdʒɛnɪsɪs/) is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. 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. In nature, mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. 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]

History

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.[5][6] The association of exposure to radiation and cancer had been observed as early as 1902, six years after the discovery of X-ray by Wilhelm Röntgen, and the discovery of radioactivity by Henri Becquerel.[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.[8] In 1940s, Charlotte Auerbach and J. M. Robson found that mustard gas can also cause mutations in fruit flies.[9]

While changes to the chromosome caused by X-ray and mustard gas were readily observable to early researchers, other changes to the DNA induced by other mutagens were not so easily observable; the mechanism by which they occur may be complex, and take longer to unravel. For example, soot was suggested to be a cause of cancer as early as 1775,[10] and coal tar was demonstrated to cause cancer in 1915.[11] The chemicals involved in both were later shown to be polycyclic aromatic hydrocarbons (PAH).[12] PAHs by themselves are not carcinogenic, and it was proposed in 1950 that the carcinogenic forms of PAHs are the oxides produced as metabolites from cellular processes.[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.

Distinction between a mutation and DNA damage

Mammalian nuclear DNA may sustain more than 60,000 damage episodes per cell per day, as listed with references in DNA damage (naturally occurring). If left uncorrected, these adducts, after misreplication past the damaged sites, can give rise to mutations. In nature, the mutations that arise may be beneficial or deleterious—this is the driving force of evolution. An organism may acquire new traits through genetic mutation, but mutation may also result in impaired function of the genes and, in severe cases, causes the death of the organism. Mutation is also a major source for acquisition of resistance to antibiotics in bacteria, and to antifungal agents in yeasts and molds.[16][17] In a laboratory setting, mutagenesis is a useful technique for generating mutations that allows the functions of genes and gene products to be examined in detail, producing proteins with improved characteristics or novel functions, as well as mutant strains with useful properties. Initially, the ability of radiation and chemical mutagens to cause mutation was exploited to generate random mutations, but later techniques were developed to introduce specific mutations.

In humans, an average of 60 new mutations are transmitted from parent to offspring. Human males, however, tend to pass on more mutations depending on their age, transmitting an average of two new mutations to their progeny with every additional year of their age.[18][19]

Mechanisms

Mutagenesis may occur endogenously (e.g. spontaneous hydrolysis), through normal cellular processes that can generate reactive oxygen species and DNA adducts, or through error in DNA replication and repair.[20] Mutagenesis may also occur as a result of the presence of environmental mutagens that induce changes to an organism's DNA, like radiation and/or radioactivity. The mechanism by which mutation occurs varies according to the mutagen, or the causative agent, involved. Most mutagens act either directly, or indirectly via mutagenic metabolites, on an organism's DNA, producing lesions. Some mutagens, however, may affect the replication or chromosomal partition mechanism, and other cellular processes. Mutagenesis may also be self-induced by unicellular organisms when environmental conditions are restrictive to the organism's growth, such as bacteria growing in the presence of antibiotics, yeast growing in the presence of an antifungal agent, or other unicellular organisms growing in an environment lacking in an 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

DNA damage and spontaneous mutation

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

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

Base deamination

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

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.

Tautomerism

Main article: Chemistry: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 (-NH2 ) 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.[32]

Modification of bases

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;[33] 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. N7 and O6 of guanine and the N3 and N7 of adenine are most susceptible to attack. N7-guanine adducts form the bulk of DNA adducts, but they appear to be non-mutagenic. Alkylation at O6 of guanine, however, is harmful because excision repair of O6-adduct of guanine may be poor in some tissues such as the brain.[34] The O6 methylation of guanine can result in G to A transition, while O4-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.[35]


See also: Biology:Epigenetics

Exogenous DNA damage

Arrows indicates chromosomal breakages due to DNA damage.

Backbone damage

Crosslinking

Main article: Biology:Crosslinking of DNA


Dimerization

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 .[36] 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;[37] 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.[38]

Intercalation between bases

Main article: Chemistry:Intercalation (biochemistry)


Insertional mutagenesis

Main article: Biology: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.[39]

DNA repair pathway

Base excision repair

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

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

Mismatch repair removes base mismatch that have arisen during replication and the insertion-deletion loop.[40] Humans employ the MutSα heterodimer (MSH2/MSH6) to recognize the base mismatch.[41] 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.[42]

Adaptive mutagenesis mechanisms

Main article: Biology: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.[43] Chromosomal events, specially gene amplification, seem also to be relevant to this adaptive mutagenesis in bacteria.[44]

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][45][46]

Laboratory applications

Main article: Biology:Mutagenesis (molecular biology technique)


Early methods of mutagenesis produced entirely random mutations; however, modern methods of mutagenesis are capable of producing site-specific mutations. Modern laboratory techniques used to generate these mutations include:

See also

References

  1. ↑ Beale, G. (1993). "The Discovery of Mustard Gas Mutagenesis by Auerbach and Robson in 1941". Genetics 134 (2): 393–399. doi:10.1093/genetics/134.2.393. PMID 8325476. 
  2. ↑ Kevin M. Gleason Published: 2017-03-07. "Hermann Joseph Muller's Study of X-rays as a Mutagen, (1926-1927)". https://embryo.asu.edu/pages/hermann-joseph-mullers-study-x-rays-mutagen-1926-1927. 
  3. ↑ "Genetics and Genomics Timeline 1927 Hermann J. Muller (1890-1967) demonstrates that X rays can induce mutations". http://www.genomenewsnetwork.org/resources/timeline/1927_Muller.php. 
  4. ↑ Muller, H. J. (1927). "Artificial Transmutation of the Gene". Science 66 (1699): 84–87. doi:10.1126/science.66.1699.84. PMID 17802387. Bibcode: 1927Sci....66...84M. http://www.esp.org/foundations/genetics/classical/holdings/m/hjm-1927a.pdf. 
  5. ↑ Crow, J. F.; Abrahamson, S. (1997). "Seventy Years Ago: Mutation Becomes Experimental". Genetics 147 (4): 1491–1496. doi:10.1093/genetics/147.4.1491. PMID 9409815. 
  6. ↑ Calabrese, E. J. (30 June 2011). "Muller's Nobel lecture on dose–response for ionizing radiation:ideology or science?". Archives of Toxicology 85 (4): 1495–1498. doi:10.1007/s00204-011-0728-8. PMID 21717110. Bibcode: 2011ArTox..85.1495C. http://users.physics.harvard.edu/~wilson/freshman_seminar/Radiation/Calabrese-Muller-1-1.pdf. Retrieved 30 December 2011. 
  7. ↑ Ronald L. Kathren (December 2002). "Historical Development of the Linear Nonthreshold Dose-Response Model as Applied to Radiation". University of New Hampshire Law Review 1 (1). https://scholars.unh.edu/unh_lr/vol1/iss1/5/. 
  8. ↑ Stadler, L. J.; G. F. Sprague (1936-10-15). "Genetic Effects of Ultra-Violet Radiation in Maize. I. Unfiltered Radiation". Proc. Natl. Acad. Sci. U.S.A. 22 (10): 572–8. doi:10.1073/pnas.22.10.572. PMID 16588111. PMC 1076819. Bibcode: 1936PNAS...22..572S. http://www.pnas.org/cgi/reprint/22/10/579.pdf. Retrieved 2007-10-11. 
  9. ↑ Auerbach, C.; Robson, J.M.; Carr, J.G. (March 1947). "Chemical Production of Mutations". Science 105 (2723): 243–7. doi:10.1126/science.105.2723.243. PMID 17769478. Bibcode: 1947Sci...105..243A. 
  10. ↑ Brown, J. R.; Thornton, J. L. (1957). "Percivall Pott (1714-1788) and Chimney Sweepers' Cancer of the Scrotum". British Journal of Industrial Medicine 14 (1): 68–70. doi:10.1136/oem.14.1.68. PMID 13396156. 
  11. ↑ "Experimentelle Studie ueber die Pathogenese der Epithel geschwuelste". Mitteilungen aus der Medizinischen Fakultät der Kaiserlichen Universität zu Tokyo 15: 295–344. 1915. 
  12. ↑ Luch, Andreas (2005). "Nature and Nurture — Lessons from Chemical Carcinogenesis: Chemical Carcinogens — From Past to Present". Medscape. http://www.medscape.com/viewarticle/499098_2. 
  13. ↑ Boyland E (1950). "The biological significance of metabolism of polycyclic compounds". Biochemical Society Symposium 5: 40–54. ISSN 0067-8694. OCLC 216723160. https://books.google.com/books?id=_kYQAQAAMAAJ. 
  14. ↑ Omura, T.; Sato, R. (1962). "A new cytochrome in liver microsomes". The Journal of Biological Chemistry 237 (4): 1375–1376. doi:10.1016/S0021-9258(18)60338-2. PMID 14482007. 
  15. ↑ Conney, A. H. (1982). "Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture". Cancer Research 42 (12): 4875–4917. PMID 6814745. http://cancerres.aacrjournals.org/content/42/12/4875.long. 
  16. ↑ 16.0 16.1 Geisinger, Edward; Vargas-Cuebas, Germán; Mortman, Nadav J.; Syal, Sapna; Dai, Yunfei; Wainwright, Elizabeth L.; Lazinski, David; Wood, Stephen et al. (2019-06-11). Miller, Samuel I.. ed. "The Landscape of Phenotypic and Transcriptional Responses to Ciprofloxacin in Acinetobacter baumannii: Acquired Resistance Alleles Modulate Drug-Induced SOS Response and Prophage Replication". mBio 10 (3). doi:10.1128/mBio.01127-19. ISSN 2150-7511. PMID 31186328. 
  17. ↑ 17.0 17.1 Quinto-Alemany, David; Canerina-Amaro, Ana; Hernández-Abad, Luís G.; Machín, Félix; Romesberg, Floyd E.; Gil-Lamaignere, Cristina (2012-07-31). Sturtevant, Joy. ed. "Yeasts Acquire Resistance Secondary to Antifungal Drug Treatment by Adaptive Mutagenesis". PLOS ONE 7 (7). doi:10.1371/journal.pone.0042279. ISSN 1932-6203. PMID 22860105. Bibcode: 2012PLoSO...742279Q. 
  18. ↑ Jha, Alok (22 August 2012). "Older fathers pass on more genetic mutations, study shows". https://www.theguardian.com/science/2012/aug/22/older-fathers-genetic-mutations-research. 
  19. ↑ Kong, A.; Frigge, M. L.; Masson, G.; Besenbacher, S.; Sulem, P.; Magnusson, G.; Gudjonsson, S. A.; Sigurdsson, A. et al. (2012). "Rate of de novo mutations and the importance of father's age to disease risk". Nature 488 (7412): 471–475. doi:10.1038/nature11396. PMID 22914163. Bibcode: 2012Natur.488..471K. 
  20. ↑ 20.0 20.1 Loeb, L. A. (1989). "Endogenous carcinogenesis: Molecular oncology into the twenty-first century--presidential address". Cancer Research 49 (20): 5489–5496. PMID 2676144. http://cancerres.aacrjournals.org/content/49/20/5489.full.pdf. 
  21. ↑ 21.0 21.1 Heidenreich, Erich (January 2007). "Adaptive Mutation in Saccharomyces cerevisiae". Critical Reviews in Biochemistry and Molecular Biology 42 (4): 285–311. doi:10.1080/10409230701507773. ISSN 1040-9238. PMID 17687670. 
  22. ↑ Quinto-Alemany, David; Canerina-Amaro, Ana; Hernández-Abad, Luís G.; Machín, Félix; Romesberg, Floyd E.; Gil-Lamaignere, Cristina (2012-07-31). Sturtevant, Joy. ed. "Yeasts Acquire Resistance Secondary to Antifungal Drug Treatment by Adaptive Mutagenesis". PLOS ONE 7 (7). doi:10.1371/journal.pone.0042279. ISSN 1932-6203. PMID 22860105. Bibcode: 2012PLoSO...742279Q. 
  23. ↑ Aghapour, Zahra; Gholizadeh, Pourya; Ganbarov, Khudaverdi; bialvaei, Abed Zahedi; Mahmood, Suhad Saad; Tanomand, Asghar; Yousefi, Mehdi; Asgharzadeh, Mohammad et al. (April 2019). "Molecular mechanisms related to colistin resistance in Enterobacteriaceae". Infection and Drug Resistance 12: 965–975. doi:10.2147/idr.s199844. PMID 31190901. 
  24. ↑ Trevor M. Penning (2011). Chemical Carcinogenesis (Current Cancer Research). Springer. ISBN 978-1-61737-994-9. 
  25. ↑ "Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium". Chemical Research in Toxicology 21 (1): 28–44. January 2008. doi:10.1021/tx700198a. PMID 17970581. 
  26. ↑ Porro, Antonio (2016-05-18). "Editorial: Grappling with the Multifaceted World of the DNA Damage Response" (in English). Frontiers in Genetics 7. doi:10.3389/fgene.2016.00091. ISSN 1664-8021. PMID 27242897. 
  27. ↑ "Impact of reactive oxygen species on spontaneous mutagenesis in Escherichia coli". Genes Cells 11 (7): 767–78. July 2006. doi:10.1111/j.1365-2443.2006.00982.x. PMID 16824196. 
  28. ↑ "DNA sequence analysis of spontaneous mutagenesis in Saccharomyces cerevisiae". Genetics 148 (4): 1491–505. April 1998. doi:10.1093/genetics/148.4.1491. PMID 9560369. PMC 1460101. http://www.genetics.org/cgi/pmidlookup?view=long&pmid=9560369. 
  29. ↑ Huertas P (January 2010). "DNA resection in eukaryotes: deciding how to fix the break". Nat. Struct. Mol. Biol. 17 (1): 11–6. doi:10.1038/nsmb.1710. PMID 20051983. 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 30.5 Chatterjee, Nimrat; Walker, Graham C. (June 2017). "Mechanisms of DNA damage, repair, and mutagenesis" (in en). Environmental and Molecular Mutagenesis 58 (5): 235–263. doi:10.1002/em.22087. ISSN 0893-6692. PMID 28485537. PMC 5474181. https://onlinelibrary.wiley.com/doi/10.1002/em.22087. 
  31. ↑ Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Morgan, David; Raff, Martin; Roberts, Keith; Walter, Peter (2017-08-07), "DNA Replication, Repair, and Recombination", Molecular Biology of the Cell (W.W. Norton & Company): pp. 237–298, ISBN 978-1-315-73536-8, https://doi.org/10.1201/9781315735368-5, retrieved 2026-04-29 
  32. ↑ Sinden, Richard R. (1994). DNA Structure and Function. Academic Press. pp. 17–20. ISBN 978-0-12-645750-6. https://books.google.com/books?id=Q6Yd-qYvx9UC&pg=PA17. 
  33. ↑ Melendez-Colon, V. J.; Smith, C. A.; Seidel, A.; Luch, A.; Platt, K. L.; Baird, W. M. (1997). "Formation of stable adducts and absence of depurinating DNA adducts in cells and DNA treated with the potent carcinogen dibenzoa, lpyrene or its diol epoxides". Proceedings of the National Academy of Sciences of the United States of America 94 (25): 13542–13547. doi:10.1073/pnas.94.25.13542. PMID 9391062. Bibcode: 1997PNAS...9413542M. 
  34. ↑ Boysen, G.; Pachkowski, B. F.; Nakamura, J.; Swenberg, J. A. (2009). "The Formation and Biological Significance of N7-Guanine Adducts". Mutation Research/Genetic Toxicology and Environmental Mutagenesis 678 (2): 76–94. doi:10.1016/j.mrgentox.2009.05.006. PMID 19465146. Bibcode: 2009MRGTE.678...76B. 
  35. ↑ Loechler, E. L. (1996). "The role of adduct site-specific mutagenesis in understanding how carcinogen-DNA adducts cause mutations: Perspective, prospects and problems". Carcinogenesis 17 (5): 895–902. doi:10.1093/carcin/17.5.895. PMID 8640935. 
  36. ↑ Setlow, R. B. (1966). "Cyclobutane-type pyrimidine dimers in polynucleotides". Science 153 (734): 379–386. doi:10.1126/science.153.3734.379. PMID 5328566. Bibcode: 1966Sci...153..379S. 
  37. ↑ Broyde, S.; Patel, D. J. (2010). "DNA repair: How to accurately bypass damage". Nature 465 (7301): 1023–1024. doi:10.1038/4651023a. PMID 20577203. Bibcode: 2010Natur.465.1023B. 
  38. ↑ Mata, Douglas A.; Williams, Erik A.; Sokol, Ethan; Oxnard, Geoffrey R.; Fleischmann, Zoe; Tse, Julie Y.; Decker, Brennan (23 March 2022). "Prevalence of UV Mutational Signatures Among Cutaneous Primary Tumors". JAMA Network Open 5 (3): e223833. doi:10.1001/jamanetworkopen.2022.3833. PMID 35319765. 
  39. ↑ Mohanasundaram, Boominathan; Rajmane, Vyankatesh B.; Jogdand, Sukanya V.; Bhide, Amey J.; Banerjee, Anjan K. (June 2019). "Agrobacterium-mediated Tnt1 mutagenesis of moss protonemal filaments and generation of stable mutants with impaired gametophyte". Molecular Genetics and Genomics 294 (3): 583–596. doi:10.1007/s00438-019-01532-4. PMID 30689096. 
  40. ↑ Chatterjee, Nimrat; Walker, Graham C. (2017-05-09). "Mechanisms of DNA damage, repair, and mutagenesis" (in en). Environmental and Molecular Mutagenesis 58 (5): 235–263. doi:10.1002/em.22087. ISSN 0893-6692. PMID 28485537. PMC 5474181. https://onlinelibrary.wiley.com/doi/10.1002/em.22087. 
  41. ↑ Chatterjee, Nimrat; Walker, Graham C. (2017-05-09). "Mechanisms of DNA damage, repair, and mutagenesis" (in en). Environmental and Molecular Mutagenesis 58 (5): 235–263. doi:10.1002/em.22087. ISSN 0893-6692. PMID 28485537. PMC 5474181. https://onlinelibrary.wiley.com/doi/10.1002/em.22087. 
  42. ↑ Chatterjee, Nimrat; Walker, Graham C. (2017-05-09). "Mechanisms of DNA damage, repair, and mutagenesis" (in en). Environmental and Molecular Mutagenesis 58 (5): 235–263. doi:10.1002/em.22087. ISSN 0893-6692. PMID 28485537. PMC 5474181. https://onlinelibrary.wiley.com/doi/10.1002/em.22087. 
  43. ↑ Aghapour, Zahra; Gholizadeh, Pourya; Ganbarov, Khudaverdi; bialvaei, Abed Zahedi; Mahmood, Suhad Saad; Tanomand, Asghar; Yousefi, Mehdi; Asgharzadeh, Mohammad et al. (April 2019). "Molecular mechanisms related to colistin resistance in Enterobacteriaceae". Infection and Drug Resistance 12: 965–975. doi:10.2147/idr.s199844. PMID 31190901. 
  44. ↑ Hersh, Megan N; Ponder, Rebecca G; Hastings, P.J; Rosenberg, Susan M (June 2004). "Adaptive mutation and amplification in Escherichia coli: two pathways of genome adaptation under stress". Research in Microbiology 155 (5): 352–359. doi:10.1016/j.resmic.2004.01.020. PMID 15207867. 
  45. ↑ Longerich, S.; Galloway, A. M.; Harris, R. S.; Wong, C.; Rosenberg, S. M. (1995-12-19). "Adaptive mutation sequences reproduced by mismatch repair deficiency.". Proceedings of the National Academy of Sciences 92 (26): 12017–12020. doi:10.1073/pnas.92.26.12017. ISSN 0027-8424. PMID 8618835. Bibcode: 1995PNAS...9212017L. 
  46. ↑ Rosenberg, Susan M.; Fitzgerald, Devon M. (2019-04-01). "What is mutation? A chapter in the series: How microbes "jeopardize" the modern synthesis". PLOS Genetics 15 (4). doi:10.1371/journal.pgen.1007995. ISSN 1553-7404. PMID 30933985. 



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