The Mechanisms of UV Mutagenesis

We have proposed calling such UV-specific mutations “solarUV signature”

Hironobu IKEHATA

2011

Scholarcy highlights

  • Ultraviolet light has strong genotoxic effects to produce DNA damage, induce mutations, and, in the worst case, cause the development of tumors
  • Non-UV-signature mutation—triplet mutation We reported that a class of UV-specific mutations, the triplet mutation, which is separate from the UV signature, is induced in mouse skin after UVB irradiation especially remarkably in the genetic backgrounds of NER deficiency.123–126) Triplet mutations were detected in a retrospective search among previous reports on studies of the UVinduced mutation spectra in mammalian cells and p53 mutations in skin cancers.127) The triplet mutation is defined as a multiple base substitution or frameshift within a three-nucleotide sequence which includes a dipyrimidine sequence.123,127) Most of the triplet mutations detected in those studies occurred at triplet sequences with a dipyrimidine at their 3’-side two bases.127) Triplet mutations appeared notably in genetic backgrounds and physiological conditions leading to NER deficiency127) suggesting that UV-induced DNA damage that causes triplet mutations should be repairable by NER
  • We have proposed a model for the induction mechanism of the triplet mutation based on errorprone translesion DNA synthesis opposite UV photolesions This model supposes that misinsertions by the TLS could occur opposite the photolesions and opposite the undamaged template base one-nucleotide downstream from the lesions, and predicts that errors could occur at the extension step as well as at the insertion step in the two-step model of UV mutagenesis mentioned above,94–96) which is consistent with the error-prone character of TLS polymerases specializing in the extension, polζ and polκ. 71,90) In addition, the pattern of base changes observed in triplet mutations suggests that the error-prone TLS causing those mutations largely follows the A-rule,63,64,127) which is consistent with the preference of polζ for a terminal mismatched nucleotide to extend from.65)
  • Three different types of base substitution characterized the UVA-induced mutation spectrum that each group insisted on. One of those base substitutions is T → G transversion, which was detected most frequently together with the less frequent UV-signature mutation after UVA irradiation and designated as “UVA fingerprint” because it was so unique as to be rarely induced by other mutagenic agents and conditions.135) Detection of the UVA fingerprint mutations was reported in a study with human skin tumors.139) T → G transversions were hardly detected in the UVA-induced mutation spectra by other groups, and the mechanism by which they are induced remains unclear, 8OH-dGTP, one of the oxidative forms of cellular nucleotides, might have induced such mutations Another type of the characteristic UVA-induced base substitution was G → T transversion, whose induction was observed at a similar frequency as the UV signature mutations after UVA1 exposure.136) This result strongly supported a major contribution of ROS to the UVA-mediated mutagenesis because G → T substitution is a representative ROS-specific mutation known to be induced by one of the most mutagenic types of oxidative DNA base damage, 8OH-G.21) the third group of the UVAinduced mutation spectra was characterized exclusively by C → T base substitutions at dipyrimidine sites, namely UV signature mutations,137,138) supporting the major contribution of cyclobutane pyrimidine dimers to the UVAinduced mutation
  • We have learned that the former pathway seems to dominate all over the UV wavelengths at least in normal cells and healthy skin. Mutagenesis with such directly produced DNA damage is mainly mediated through mechanisms based on TLS, for which two models have been proposed: the model of “errorfree” bypass of a deaminated cytosine-containing CPD by polη, and the model of error-prone two-step bypass, which consists of misinsertion andextension steps, by multiple TLS/replicative polymerases
  • The two-step model should be relevant to the mutagenicity of 64PP and Dewar isomer, and could explain the triplet mutation, one of the UV-specific non-UV-signature mutations, the contributing polymerases and causative DNA damage remain to be clearly identified
  • Mutagenesis with such directly produced DNA damage is mainly mediated through mechanisms based on translesion DNA synthesis, for which two models have been proposed: the model of “errorfree” bypass of a deaminated cytosine-containing cyclobutane pyrimidine dimers by polη, and the model of error-prone two-step bypass, which consists of misinsertion andextension steps, by multiple TLS/replicative polymerases

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