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

Abstract

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.