Mutagenesis Mechanisms


Deoxyribonucleic acid (DNA), the keeper of genetic information in all organisms, is constantly modified by internal and external factors during the cell's lifetime. Many types of DNA modification cause mutations. Although mutations may be harmful to individual cells or organisms, mutation in populations is valuable because it leads to genetic variation and ultimately to evolution. There are even circumstances when it is useful to increase the number of mutations in a cell. Maintaining the optimum balance between genetic stability and variability requires the cell to regulate both the frequency with which modifications to the DNA occur, and the efficiency with which the original sequence is restored by the various DNA repair pathways. One group of cellular enzymes, the DNA polymerases, plays a key role in both mutation occurrence and mutation avoidance. In this article we consider how mutations occur in DNA, and how cells regulate their mutation rate, with an emphasis on the role of the DNA polymerases.

Key Concepts:

  • Modification of DNA structure is the first step in the pathway to mutation.

  • Most structural changes in DNA are caused by normal physiological processes.

  • Mutation frequency depends on the frequency of DNA structural change and the efficiency of DNA repair processes.

  • DNA polymerase is the key enzyme of mutagenesis.

  • Mutations are a cause of genetic disease.

  • Mutations are the raw material for evolution.

  • To ensure survival, cells must maintain the optimal balance between genetic stability and variability.

Keywords: mutagenesis; frameshift; base substitution; transition; transversion; DNA polymerase; DNA repair; missense mutation; nonsense mutation; error catastrophe

Figure 1.

Role of DNA polymerases in causing and preventing mutations.

Figure 2.

Base substitution mutations are caused by mismatches. The eight possible base pair mismatches are responsible for the six base substitution mutations: two transitions and four transversions. Note that the second transition mutation (GC‐to‐AT) (not shown) is simply the reverse mutation to the AT‐to‐GC mutation (illustrated); A‐C and G‐T mismatches are common intermediates for both. Likewise, A‐G and C‐T mismatches are the common intermediates for both the AT‐to‐CG transversion (illustrated) and for the reverse CG‐to‐AT transversion (not shown).

Figure 3.

Origin and biological effects of point mutations. (a) Spontaneous deamination (the loss of an amino group) converts methylated cytosines into thymines. If the resulting T‐G mismatch is not repaired before the DNA replicates, the T normally pairs with an A, resulting in a CG‐to‐TA transition mutation. In the example shown here, this leads to the substitution of a leucine for a proline in the protein product of the mutated gene (a missense mutation). (b) If damaged bases in the DNA are removed, an abasic site results. When DNA polymerase, the enzyme which copies DNA, encounters such a site it usually inserts an A in the new DNA strand. Unless the original damaged base was a T, this results in a mutation like the CG‐to‐TA transition shown here. In this example both the original CAC codon and the new CAT codon code for a histidine so the protein product of this mutated gene is unaltered. (c) DNA replication errors may result in unpaired bases. Unrepaired, these lesions produce frameshift mutations (the loss or gain of one or two bases). Such alterations in the DNA frequently lead to the formation of nonsense codons, such as the TAG codon shown here. Nonsense codons terminate translation, resulting in the production of truncated proteins.

Figure 4.

The polymerase‐switching model for TLS. When a replication fork is blocked by a DNA lesion, the replicative polymerase leaves the complex and is replaced by a TLS polymerase. Sometimes this process requires the sequential participation of two different TLS polymerases. The TLS polymerase bypasses the lesion, after which it leaves the complex and the replicative polymerase returns to its place.

Figure 5.

Somatic hypermutation. AID deaminates single‐stranded DNA formed during transcription, creating a U‐G mismatch. This mismatch can be resolved by several pathways, each of which is mutagenic. Left: immediate DNA replication without repair of the U results in CG‐to‐TA transitions; middle: removal of the U by the UNG glycosylase and apurinic endonucleases (APE's) results in an abasic site. If this base excision repair (BER) process is not completed before DNA replication, the polymerase inserts bases at random opposite the abasic site, resulting in mismatches. Alternatively, AP endonuclease may remove the abasic site, leaving a gap that may be repaired by a mismatch‐generating TLS polymerase. Lack of repair of the mismatches results in various transition and transversion mutations during future rounds of DNA replication; right: initiation of mismatch repair (MMR) removes the U along with many surrounding bases. Resynthesis of the missing strand by an error‐prone DNA polymerase, pol η, results in mutations not only at the original site of deamination but also in the surrounding sequence.



Chuang JH and Li H (2004) Functional bias and spatial organization of genes in mutational hot and cold regions in the human genome. PLoS Biology 2(2): E29.

Foster PL (2007) Stress‐induced mutagenesis in bacteria. Critical Reviews in Biochemisrty and Molecular Biology 42(5): 373–397.

Fox EJ, Beckman RA and Loeb LA (2010) Reply: is there any genetic instability in human cancer? DNA Repair (Amsturdam) 9(8): 859–860.

Janion C (2008) Inducible SOS response system of DNA repair and mutagenesis in E. coli. International Journal of Biolological Sciences 4(6): 338–344.

Jayaraman R (2009) Mutators and hypermutability in bacteria: the E. coli paradigm. Journal of Genetics 88(3): 379–391.

Jun SH, Kim TG and Ban C (2006) DNA mismatch repair system. Classical and fresh roles. FEBS Journal 273(8): 1609–1619.

Layton JC and Foster PL (2003) Error‐prone DNA polymerase IV is controlled by the stress‐response sigma factor, RpoS, in E. coli. Molecular Microbiology 50(2): 549–561.

Linde L and Kerem B (2008) Introducing sense into nonsense in treatments of human genetic diseases. Trends in Genetics 24(11): 552–563.

Loeb LA (2001) A mutator phenotype in cancer. Cancer Research 61(8): 3230–3239.

Moxon R, Bayliss C and Hood D (2006) Bacterial contingency loci: the role of simple sequence DNA repeats in bacterial adaptation. Annual Review of Genetics 40: 307–333.

Patel M, Jiang Q, Woodgate R, Cox MM and Goodman MF (2010) A new model for SOS‐induced mutagenesis: how RecA protein activates DNA polymerase V. Critical Reviews in Biochemistry and Molecular Biology 45(3): 171–184.

Peled JU, Kuang FL, Iglesias–Ussel MD et al. (2008) The biochemistry of somatic hypermutation. Annual Review of Immunology 26: 481–511.

Pfeifer GP (2000) p53 mutational spectra and the role of methylated CpG sequences. Mutation Research 450(1–2): 155–166.

Pitsikas P, Patapas JM and Cupples CG (2004) Mechanism of 2‐aminopurine‐stimulated mutagenesis in E. coli. Mutation Research 550(1–2): 25–32.

Smith RA, Loeb LA and Preston BD (2005) Lethal mutagenesis of HIV. Virus Research 107(2): 215–228.

Waters LS, Minesinger BK, Wiltrout ME et al. (2009) Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance. Microbiology and Molecular Biology Review 73(1): 134–154.

Zuccato C, Valenza M and Cattaneo E (2010) Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiological Review 90(3): 905–981.

Further Reading

Friedberg EC, Walker GC, Siede W et al. (2005) DNA Repair and Mutagenesis, 2nd edn. Washington DC: ASM Press.

Hakem R (2008) DNA‐damage repair; the good, the bad, and the ugly. EMBO Journal 27(4): 589–605.

Hubscher U, Maga G and Spadari S (2002) Eukaryotic DNA Polymerases. Annual Review of Biochemistry 71: 133–163.

Loeb L and Monnat R (2008) DNA polymerases and human disease. Nature Reviews. Genetics 9: 594–604.

Tost J (2010) DNA methylation: an introduction to the biology and the disease‐associated changes of a promising biomarker. Molecular Biotechnology 44(1): 71–81.

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How to Cite close
Polosina, Yaroslava Y, and Cupples, Claire G(Feb 2011) Mutagenesis Mechanisms. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000837.pub2]