Cancer Letters

Cancer Letters

Volume 327, Issues 1–2, 31 December 2012, Pages 5-15
Cancer Letters

Mini-review
Oxidatively generated complex DNA damage: Tandem and clustered lesions

https://doi.org/10.1016/j.canlet.2012.04.005Get rights and content

Abstract

There is an increasing interest for oxidatively generated complex lesions that are potentially more detrimental than single oxidized nucleobases. In this survey, the recently available information on the formation and processing of several classes of complex DNA damage formed upon one radical hit including mostly hydroxyl radical and one-electron oxidants is critically reviewed. The modifications include tandem base lesions, DNA-protein cross-links and intrastrand (purine 5′,8-cyclonucleosides, adjacent base cross-links) and interstrand cross-links. Information is also provided on clustered lesions produced essentially by exposure of cells to ionizing radiation and high energetic heavy ions through the involvement of multiple radical events that induce several lesions DNA in a close spatial vicinity. These consist mainly of double strand breaks (DSBs) and non-DSB clustered lesions that are referred as to oxidatively generated clustered DNA lesions (OCDLs).

Introduction

Oxidative stress results from the imbalance between endogenous generation of reactive oxygen species (ROS) and anti-oxidant defence systems [1] that involve scavenging of low reactive ROS such as superoxide radical (O2-) and hydrogen peroxide (H2O2), the precursors of highly damaging hydroxyl radical (radical dotOH) [2]. These oxygen species may be triggered by inflammation reactions [3], [4] that also lead to the exalted production of nitric oxide [5], [6], one of the main nitrogen reactive species (NOS). Oxidative stress have been shown to be associated with physical exercise [7], metal toxicities [8], aging [9], [10] and several pathologies including mellitus diabetis [11], cardiovascular diseases [12], [13], neurological disorders [14], [15] and cancers [16], [17], [18], [19], [20]. Exacerbated generation of ROS and other oxidizing processes such as one-electron oxidation of biomolecules are also provided by ionizing radiation [21], [22] and the UVA component of solar light [23], [24], two well established physical carcinogens. DNA is the main critical cellular target to oxidatively generated damage that may participate in the initiation and/or propagation processes leading to carcinogenesis through mutagenesis [17], [18], [19], [20], [25]. An abundant literature is now available on the mechanisms of oxidative degradation of nucleobases [26], [27], [28], [29] and 2-deoxyribose [30] in isolated DNA and model compounds that are mediated by radical dotOH, singlet oxygen (1O2) and one-electron oxidants, the three main identified reactive oxidizing species and agents. The measurement of oxidized bases in cellular DNA has been hampered until the end of the 1990s by the use of inappropriate methods that has led to overestimation of the levels of oxidized bases up to three orders of magnitude [31]. Accurate data are now available on the formation of several oxidatively generated base lesions including ubiquitous 8-oxo-7,8-dihydroguanine (8-oxoGua) and thirteen single oxidized purine and pyrimidine bases in cellular DNA. This may be achieved for electrochemically active lesions including 8-oxoGua, 8-oxo-7,8-dihydroadenine (8-oxoAde) and 5-hydroxycytosine using high-performance liquid chromatography coupled to electrochemical detection (HPLC-ECD) as the analytical method. However, the method of choice appears to be HPLC associated with electrospray ionization tandem mass spectrometry (ESI-MS/MS) as a versatile and accurate method [31]. Information on the mutagenic features of several single base lesions has been gained from shuttle vector experiments [32], [33] and polymerase-mediated incorporation into DNA of oxidized precursors present in the nucleotide pools [34]. Major efforts have been also devoted to the determination of substrate specificity and removal mechanisms of repair enzymes that mostly operate for single lesions through the base excision repair pathways [35], [36]. The radiation-induced formation of locally multiply damaged sites, also referred as to oxidatively generated clustered lesions (ODCLs) [37], [38] was suggested more than 25 years ago in addition to previously identified double strand breaks (DSBs) [39], [40]. The formation of these complex lesions that may include DSBs, single strand breaks (SSBs), oxidized bases and abasic sites, is accounted for by the occurrence of at least two radical hits within one or two helix turns [41], [42]. Following the pioneering contributions of Box and collaborators in the 1990s [43] it was found that tandem base modifications can be generated in DNA consecutively to the initial formation of peroxyl pyrimidine radicals that subsequently react with vicinal bases [44]. Other types of complex damage whose formation involves a single initial radical hit include DNA-protein cross-links, intra- and interstrand DNA cross-links [28]. In this short review article emphasis is placed on recent aspects of the formation of non-single oxidatively generated damage in cellular DNA that receive increasing attention due to their deleterious biological potential [45].

Section snippets

Hydroxyl radical and one-electron oxidants as inducers of complex DNA damage

As already briefly mentioned, the oxidation reactions indentified so far in DNA may be mostly explained in terms of initial involvement of radical dotOH, one-electron oxidant or 1O2. It is now well documented that 1O2 reacts specifically with guanine producing 8-oxoGua in cellular DNA at the exclusion of rearrangement products [23], [27], [46]. As a result, the lack of formation of the reactive quinonoid intermediate that is observed in free 2′-deoxyguanosine upon [4 + 2] cycloaddition of 1O2 to the purine

Tandem base modifications

Two main types of tandem base modifications have been shown to be generated by one radical hit that may involve radical dotOH and/or one-electron oxidants. Subsequently, either pyrimidine centered radicals or related pyrimidine peroxyl radicals thus generated are able to react with the adjacent base. The efficiency of the intramolecular reaction is higher when the target base is located on the 5′-side with respect to the reactive pyrimidine radicals. This may be rationalized in terms of shorter distances

Multiple radical hit-induced clustered DNA damage

It is well documented that energy deposition along the track of 200 keV–1 MeV photons leads to the generation of radical dotOH, ionization events and secondary electrons in a very close vicinity. This gives rise when the nucleus is the target of either ionizing radiation or heavy ions to the formation of complex types of damage including double strand breaks (DSBs) and non-DSB oxidatively generated clustered DNA lesions (OCDLs) through transient multiple radical and excitation events [21], [22], [41], [142].

Conclusions

Relevant information has been gained on the oxidative formation of complex types of DNA damage as the result of either one hit or several simultaneous radical events within a localized part of DNA. Relevant mechanistic insights have been obtained on the formation of DNA-protein and DNA-DNA cross-links that is based on a reasonable hypothesis involving in both cases nucleophilic addition to the guanine radical cation. This is further supported by the identification of intrastrand cross-links

Acknowledgements

The authors are grateful to the “Association pour la Recherche sur le Cancer-ARC” (Grant 1424/2011 to DA), Agence Nationale de la Recherche (grant ANR-09-PIRI-0022 (to J-LR and MTP), Electricité de France (to J-LR) and CEA Eurotalents program (to MTP) for financial support. JC is member of EU network COST Action CM0603 “Free Radicals in Chemical Biology”.

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