**1. Introduction**

96 Selected Topics in DNA Repair

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Preservation of the integrity of the DNA, carrier of heritage information, is crucial for cell survival. Altered genetic information could lead to major perturbations in cell organization, function and proliferation of cancer cells. Because cancer cells are highly proliferative with high number of replication, DNA was the first clinically used anti-cancer therapeutic target with the drugs directly (intercalators/alkylating drugs) or indirectly (micro-tubules, topoisomerases inhibitors, modifiers of histone acetylation...) targeting DNA. Despite the actual development of targeted chemotherapies (against membrane receptors, kinases, the proteasome,…), direct DNA targeting drugs still represent a major part of the actual anticancer pharmacopeia in terms of total prescriptions and efficacy. Compounds mainly bind DNA in three different ways: non-covalent (fitting in major or minor grooves), intercalation between two successive base pairs, or covalent bonding to a base, and generally lead to a stabilization of the DNA double helix. Only a few number from intercalating and alkylating families destabilizes the DNA helix. Cytotoxic effects of alkylating agents (used/developed for chemotherapy or from carcinogens) are strongly attenuated by the cellular DNA repair processes. Optimal use of DNA alkylating drugs in therapy requires a clear understanding of their DNA repair processes. Similarly, knowing how cells cope with the carcinogensinduced DNA damages is of major interest regarding health in our actual society, so prompt to use chemical compounds insufficiently studied for long term toxicities and sometimes eventually identified as carcinogens (food and industries). DNA repair processes infer with both those Yin and Yang aspects of alkylating compounds using different machineries: base excision repair (BER); nucleotide excision repair (NER: long/short-patch, transcriptioncoupled/global genome); mismatch repair (MMR); homologous recombination (HR) or nonhomologous end-joining (NHEJ). Fanconi anemia (FA) repair acts as a coordinator of those repair pathways (Moldovan & D'Andrea, 2009). Since there are yet various complete reviews on DNA repair processes in the literature, the present review will focus on the repair process of DNA destabilizing compounds.

DNA Helix Destabilization by Alkylating Agents: From Covalent Bonding to DNA Repair 99

Fig. 1. DNA intercalators that destabilize the DNA helix: structures and 3D orientation of morpholino-doxorubicin (Top, [mmdbId:52942]) or ellipticine (Bottom, [mmdbId:52189]).

Some DNA alkylating drugs could also locally destabilize DNA double helix. Some of those are used/developed as anticancer drugs such as cisplatin and metal-derivatives, or more recently the benzoacronycine derivative S23906-1. They contrast with most DNA alkylating agents used or not in chemotherapy that stabilize DNA helix (for instance mitomycin C, dinuclear platinum, nitrogen mustards or ecteinascidine 743) (Basu et al., 1993; David-Cordonnier et al., 2005; Fridman et al., 2003; Kasparkova et al., 1999). Electrophilic alkylating drugs react at nucleophilic positions of G-C or A-T bp with preferential targets: N7 position of dG or dA and O6 position of dG in the major groove, N3 positions of dG or dA and

exocyclic NH2 group on C2 of dG (also called N2) in the minor groove (Figure 2).

Fig. 2. Position of the reactive sites of some DNA alkylators on G-C or A-T base pairs.

**2.2 DNA alkylators as helix destabilizing agents** 
