Tandem double CC-->TT mutations are produced by reactive oxygen species.

Abstract

Oxidative damage to DNA is mutagenic and thus may play a role in carcinogenesis. Because of the large number of different DNA lesions formed by oxidative species, no genetic alteration so far identified is exclusively associated with oxygen damage. Tandem double CC --TT mutations are known to occur via UV damage to DNA and are thought to be a specific indicator of UV exposure. Using a sensitive reversion assay that can detect both single and double mutations within the same codon of the M13-encoded lacZa gene, we show that treatments that produce reactive oxygen species can also produce tandem double CC -k TT mutations. The frequency at which these mutations occur is less than that for single base mutations by a factor of approximately 30. The induction of these mutations is inhibited by treatment that scavenges hydroxyl radicals. This unique mutation provides a marker of oxygen free radical-induced mutagenesis in cells that are not exposed to UV-irradiation and an indicator for assessing the involvement of oxidative damage to DNA in aging and tumor progression.

Identification and Quantification of a Guanine−Thymine Intrastrand Cross-Link Lesion Induced by Cu(II)/H2O2/Ascorbate

“…In this respect, the most frequently observed mutations resulting from ROSinduced DNA damage are C→T transitions and G→T transversions (4). In addition, unusual tandem double mutations, that is, CC→TT and mCG→TT substitutions, have been shown to be induced by ROS generated from a variety of systems (4)(5)(6)(7). It was suggested that ROSinduced intrastrand crosslink lesions formed between adjacent nucleotides might contribute to the tandem base mutations (5,6).…”

DNA base damage induced by ionizing radiation recognized byEscherichia coli UvrABC nuclease but not Nth or Fpg proteins

“…Such lesions could account for tandem double CC+,'IT mutations that are known to result from damage induced by Fez+, Cu", and Ni2+ ions and also y irradiation [52-561. These mutations have also been found in the p53 gene of skin squamous cell carcinomas [5 71 and have been proposed as a marker to assess oxidative DNA damage during aging or tumor progression [54].…”

Tandem-base mutations occur in mouse liver and adipose tissue preferentially as G:C to T:A transversions and accumulate with age

“…TBM are associated most commonly with ultraviolet light, appearing as CC to TT transitions [Hutchinson, 1994]. Bisulfite [Chen and Shaw, 1994] and reactive oxygen species [Reid and Loeb, 1993] have also been shown to cause CC to TT TBM, while acetaldehyde [Matsuda et al, 1998] and cis-diamminedichloroplatinum (II) [Bubley et al, 1991] cause GG to TT TBM. All mice were housed in isolated air-filtered cages within a barrier facility, thereby minimizing any air-borne mutagens.…”