Document pmo5L86OB4JOwGEeQNRZrqONX

G Model CBI-6102; No. of Pages 4 ARTICLE IN PRESS Chemico-Biological Interactions xxx (2010) xxxxxx Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint The role of DNA repair in benzene-induced carcinogenesis Andrea Hartwig Fachgebiet Lebensmittelchemie und Toxikologie, Institut fr Lebensmitteltechnologie und Lebensmittelchemie, Technische Universitt Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany article info Article history: Available online xxx Keywords: Benzene DNA repair genomic instability abstract Benzene is a well-known human carcinogen, but the ultimate mode of action is still not known. Several reactive metabolites have been identified, including benzene oxide, phenol, hydrochinone, catechol and benzoquinones, generating different types of DNA lesions. Furthermore, the latter three metabolites may lead to the formation of reactive oxygen species (ROS) due to redox cycling, which give rise to oxidative DNA lesions and altered signaling pathways. Also, the inhibition of DNA topoisomerase II may result in DNA double strand breaks. Even though the exact contribution of the respective metabolites to benzeneinduced carcinogenicity is not yet resolved, the major DNA repair pathways such as base excision repair (BER), nucleotide excision repair (NER) and double strand break (DSB) repair are involved in the removal of benzene-induced DNA lesions. The observed target organ specificity may result from increased adduct formation, but also from poor repair in bone marrow progenitor cells. While especially excision repair pathways are predominantly error-free and thus protective, DSB repair is largely error prone and may contribute to benzene-induced genomic instability. 2010 Published by Elsevier Ireland Ltd. 1. Introduction Benzene is a known human carcinogen. Most prominent target organ is the bone marrow, leading to haematoxicity and leukemia, especially acute myeloid leukemia (AML). Unlike many other carcinogens, which either directly react with DNA or where one or few mutagenic metabolites are thought to be responsible for the carcinogenic action, benzene is not a classical mutagen, but several DNA reactive metabolites are formed. In vivo, benzene is metabolized by CYP 2E1 in the liver, yielding benzene oxide in the first step, which is further converted into phenol, catechol, hydrochinone and 1,2,4-trihydroxybenzene. Furthermore, the ring may be opened to yield mucondialdehyde and muconic acid. These metabolites formed in the liver are thought to be distributed via blood in the body and undergo secondary peroxidase-mediated metabolism in the bone marrow. Here, catechol and hydroquinone are converted to o- and p-benzochinone, respectively, and especially p-benzoquinone is thought to contribute significantly to myelotoxicity. p-Benzoquinone binds extensively to proteins and to a lesser extent also to DNA. Furthermore, the enhanced formation of ROS due to redox cycling of benzoquinones as well as glutathione-derived benzoquinone thiol conjugates contribute to benzene-induced genotoxicity; the latter have been identified in the bone marrow of rats and mice exposed to a combination of hydroquinone/phenol or benzene [15]. Also, the different E-mail address: andrea.hartwig@tu-berlin.de. 0009-2797/$ see front matter 2010 Published by Elsevier Ireland Ltd. doi:10.1016/j.cbi.2009.12.029 metabolites appear to act synergistically: thus, the formation of benzoquinone is enhanced in the presence of phenol, and a combination of the metabolites catechol, hydroquinone and phenol have been shown to trigger increased oxidative DNA damage and genotoxicity [6]. Nevertheless, also interactions with proteins may lead to DNA damage. Thus, especially p-benzochinones as well as trans,trans-muconaldehyde have been shown to inhibit topoisomerase II, generating DNA double strand breaks. The same effect has been observed with all phenolic metabolites in the presence of an activation system containing a peroxidase and hydrogen peroxide [7,8]. Nevertheless, whether or not the respective DNA lesions will contribute to benzene-induced carcinogenicity, depends strongly on their further fate, i.e. the cellular response systems activated. DNA lesions interfere with DNA transcription and replication; potential consequences are cell cycle arrest, programmed cell death, mutagenesis, genomic instability and cancer. To maintain genomic stability, a complex network of different repair systems has evolved. The major pathway eliminating DNA base damage is the excision repair pathway, subdivided into NER and BER. NER is the most versatile repair system involved in the removal of structurally unrelated bulky base adducts which cause significant helical distortions. At least 30 different proteins and enzymes are required in mammalian cells, including those which are defective in patients suffering from the DNA repair disorder Xeroderma Pigmentosum (XP) complementation groups A through G. Most of them are involved in the damage recognition and the incision at both sides of the lesion, followed by the repair polymerisation leading to the displacement of the damaged oligonucleotide and finally Please cite this article in press as: A. Hartwig, The role of DNA repair in benzene-induced carcinogenesis, Chem. Biol. Interact. (2010), doi:10.1016/j.cbi.2009.12.029 G Model CBI-6102; No. of Pages 4 2 ARTICLE IN PRESS A. Hartwig / Chemico-Biological Interactions xxx (2010) xxxxxx the ligation of the repair patch. Some forms of DNA base damage are recognized by a specific class of DNA repair enzymes called glycosylases, initiating BER. DNA glycosylases act specifically on one or few substrates, and BER is mainly responsible for the removal of different types of endogenous DNA damage, including oxidative DNA base modifications arising for example due to leakage of ROS from the electron transport chain. This process generates sites of base loss called apurinic or apyrimidinic (AP) sites, which are further processed in a multistep process with slight differences depending on the type of damage (reviewed in [9,10]). DSB are repaired by homologous recombination (HR) or nonhomologous end-joining (NHEJ). Besides DNA repair systems, further DNA damage responses are operative in mammalian cells. They include cell cycle control mechanisms, increasing the time for DNA repair, as well as apoptosis eliminating heavily damaged cells. The DNA damage response is strictly coordinated, for example by the tumor suppressor protein p53. While DNA excision repair systems are predominantly errorfree, DNA damage persisting at the time of DNA replication may also be converted into mutations due to error-prone bypass mechanisms. Also, DNA double strand break repair may be highly error prone, especially NHEJ. Thus, with respect to benzene, the impact of DNA repair in benzene-induced carcinogenicity will depend on the type and frequency of lesions, on the respective DNA repair systems involved in their removal and on the repair capacity of the target organ; these aspects will be addressed within this review. 2. Repair systems involved in the removal of defined benzene-induced DNA lesions With respect to benzene metabolites, different DNA repair systems appear to be involved in the removal or processing of relevant DNA lesions. As stated above, p-benzoquinone appears to be the most DNA reactive metabolite. It has been shown to form exocyclic DNA adducts between the N1 and N6 of adenine (1, N6-pBQ-dA), the N3 and N4 of cytosine (3,N4-pBQ-C) and the N1 and N2 of guanine (1,N2-pBQ-G); the latter lesion is also induced by hydrochinone [1113]. These lesions are recognized by the major human apurinic/apyrimidinic (AP) endonuclease (APE1 alias APEX, Ref-1 or HAP1) as well as by the bacterial exonuclease III and endonuclease IV, enzymes usually recognizing and incising AP sites in the process of BER [11,12]. Nevertheless, mutation analysis using a shuttle vector system revealed also a higher mutagenicity of pbenzoquinone-induced DNA damage processed in NER deficient human fibroblasts as compared to NER proficient cells, pointing to a role of NER in the removal of p-benzoquinone-induced DNA damage, but not of hydrochinone-induced DNA damage [14]. Furthermore, catechol quinones can react with DNA by 1,4-Michael addition to form depurinating N3-Ade and N7-Gua adducts, which may be converted into mutations by error-prone BER [15]. As stated above, besides specific DNA adducts generated by benzene metabolites, oxidative DNA damage due to redox cycling appears to play a major role in benzene-induced DNA damage [13,5]. Thus, when catechol or hydroquinone is oxidized in the presence of oxygen, superoxide (O2-) is formed, which is converted to hydrogen peroxide (H2O2) by superoxide dismutase. While both species are not able to damage DNA directly, in the presence of transition metal ions like iron or copper, H2O2 is converted to highly reactive hydroxyl (OH) radicals, which readily react with lipids, proteins and DNA. Oxidative DNA damage induced by ROS includes a broad range of lesions like DNA base modifications, sugar lesions, DNA single- and double-strand breaks, DNAprotein crosslinks and abasic sites. By applying ionizing radiation as a source for OH radicals and isolated DNA or isolated chromatin, about 100 different lesions have been identified by gas chromatography/mass spectrometry (GC/MS), including 8-oxo-7,8-dihydroguanine (8-oxo-Gua), the ring opened bases 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-guanine) and 4,6-diamino-5-formamidopyrimidine (Fapy-adenine), 8-oxoadenine, 2-hydroxyadenine, 5-hydroxymethyluracil, 5hydroxycytosine, cytosine glycol and thymine glycol [16]. Among these, 8-oxo-Gua is one of the major DNA base modifications and has attracted special attention, since in cellular systems it is mutagenic by causing G to T transversions upon replication [17] and has early been suggested to play an important role in carcinogenesis [18]. It is generally assumed that BER is quantitatively the most important repair pathway for small oxidative lesions [19], and especially the human 8-oxoguanine DNA glycosylase 1 (hOGG1). hOGG1 is involved in the removal of 8-oxo-Gua opposite C. Additionally, the glycosylases NEIL-1 and NEIL-2 have been recently identified, which show preference for removing oxidative DNA base modifications from DNA bubbles, indicating their role in the repair of oxidative DNA damage during replication and/or transcription [19]. When mispaired with A, a separate DNA glycosylase, MutY homolog, removes the A residue enabling again excision by OGG1. With respect to the removal of potentially cytotoxic pyrimidine damage such as thymine glycol and cytosine glycol, in human cells a glycosylase called hNth1 exists. Interestingly, this enzyme appears to require the NER protein XPG as a cofactor, providing a role of both BER and NER in the repair of oxidative DNA damage [20]. Also NER could function as back-up repair system in case of diminished BER [21], and mechanistic studies imply a role of sequence-dependent transcription-coupled repair of 8-oxo-Gua as well [22]. In addition to excision repair pathways, DNA double strand break (DSB) repair appears to be important in benzene-induced genotoxicity and hematotoxicity. DNA double strand breaks can arise either directly via ROS or indirectly via inhibition of topoisomerase II. DSBs are severe DNA lesions since both DNA strands are affected, leading to cell death or a variety of genetic alterations, including large- or small-scale deletions, loss of heterozygocity, translocations, and chromosome loss, thus enhancing genome instability, which is a hallmark of cancer cells. DSBs are repaired by either non-homologous end-joining (NHEJ) or by homologous recombination (HR). While the former is usually thought to be error prone by causing small deletions or small insertions, HR may be accurate if the repair template is perfectly homologous. However, on cellular conditions this dissection may be an oversimplification, and both pathways contribute to genome stability by posing risks of large- and small-scale genome rearrangements [23]. With respect to benzene, the occurrence of DSBs was detected by an increased level of phosphorylated histone H2AX (H2AX), and the Werner syndrome protein (WRN), one central component of both NHEJ and HR, was shown to protect from hydroquinone-induced DNA damage [24]. Concerning DSBs derived as a consequence of topoisomerase II inhibition, current evidence suggests that they are repaired predominantly by NHEJ, given rise to illegitimate recombination also at breakpoint cluster regions of the human AML1 gene and thus to genomic instability [25]. 3. Potential relevance of DNA lesions and their repair for realistic exposure conditions As evident from what is summarized above, a broad spectrum of DNA lesions is formed, and different DNA repair systems are involved in their removal. Nevertheless, since DNA damage is generated in several tissues, the question arises whether the induction and/or processing of DNA lesions may explain the bone marrow as target organ of benzene-induced carcinogenicity. Indeed, some factors related to DNA damage induction and repair may contribute to this target organ specificity. Thus, even though the Please cite this article in press as: A. Hartwig, The role of DNA repair in benzene-induced carcinogenesis, Chem. Biol. Interact. (2010), doi:10.1016/j.cbi.2009.12.029 G Model CBI-6102; No. of Pages 4 ARTICLE IN PRESS A. Hartwig / Chemico-Biological Interactions xxx (2010) xxxxxx 3 Fig. 1. DNA repair systems involved in the removal of benzene-induced DNA lesions and their fidelity. BER: base excision repair; NER: nucleotide excision repair; HR: homologous recombination; NHEJ: nonhomologous end-joining; SSB: DNA single strand breaks; DSB: DNA double strand breaks. overall binding of benzene metabolites to DNA is weak relative to other carcinogenic agents, time-integrated DNA adduct levels in bone marrow of benzene-treated mice are significantly higher as compared to the liver over a wide dose-range, mainly due to kinetic differences in their removal [26]. Furthermore, more detailed investigations on the occurrence of DNA strand breaks and oxidative DNA base modifications recognized by the bacterial formamidopyrimidine-DNA glycosylase (Fpg) in benzene-treated mice revealed an increase in DNA strand breaks in both liver and bone marrow, while elevated levels of Fpg-sensitive DNA base modifications were restricted to the bone marrow [27]. One other issue which has been addressed in several studies relates to the impact of inflammation on bone marrow related DNA damage. Thus, for example the extent of DNA strand breaks but not of Fpg-sensitive sites, was enhanced by the inflammatory response promoted by lipopolysaccharides [27]. Besides differences in DNA damage induction, differences in DNA repair have to be considered. When comparing primary human hematopoietic cells, CD34+ progenitor cells showed consistently lower repair capacities as compared to more differentiated CD34- cells of the same donor. Detailed mechanistic studies demonstrated that both BER and NER are affected [28]. Also, stem cells in bone marrow undergo active cell proliferation and differentiation throughout life and are thus particularly sensitive to DNA damaging factors. Finally, the DNA lesions are not only subject of error-free repair systems, but may also be processed by error-prone mechanisms, most evident for apurinic sites and DSB (Fig. 1). Many findings are derived from mechanistic studies in cell culture systems, however, there are also strong indications on the relevance especially of DNA doublestrand break repair from benzene-exposed humans. Thus, several polymorphisms in DNA repair genes have been reported to increase the susceptibility to hematotoxicity in benzene-exposed workers. They include BLM, WRN, RAD51, TP53 and WDR79, all associated with, but not limited to, DNA double strand break repair and leading to significant reductions in white blood cell count [29,30]. Also, a significantly higher sensitivity towards the induction of ionizing radiation-induced chromosomal aberrations has been observed in peripheral lymphocytes derived from benzene-exposed laboratory workers and gasoline service attendants in Thailand [31]; whether or not this is due to a lower DNA repair capacity due to benzene exposure needs further attention in the future. 4. Conclusions and perspectives In spite of extensive research on benzene-induced carcinogenicity, the ultimate mechanisms leading to leukemia have still to be identified. Benzene gives rise to several reactive metabolites, which cause a broad spectrum of DNA damage, including oxidative DNA lesions, DNA adducts and apurinic sites. Thus, functioning DNA repair systems are highly required as evident not only from mechanistic studies, but also from animal studies and the impact of repair gene polymorphisms on hematotoxicity in benzene-induced workers. Furthermore, the DNA is not the only target; several metabolites may interfere with proteins involved in maintaining DNA integrity and genomic stability. This has been demonstrated most clearly for the inhibition of topoisomerase II leading to DNA double strand breaks; other mechanisms potentially contributing to carcinogenicity are transcription factor overexpression, oncogene activation and cell signalling [1]. 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