DNA Damage Induced by Alkylating Agents and Repair Pathways

Abstract

The cytotoxic effects of alkylating agents are strongly attenuated by cellular DNA repair processes, necessitating a clear understanding of the repair mechanisms. Simple methylating agents form adducts at N- and O-atoms. N-methylations are removed by base excision repair, AlkB homologues, or nucleotide excision repair (NER). O6-methylguanine (MeG), which can eventually become cytotoxic and mutagenic, is repaired by O6-methylguanine-DNA methyltransferase, and O6MeG:T mispairs are recognized by the mismatch repair system (MMR). MMR cannot repair the O6MeG/T mispairs, which eventually lead to double-strand breaks. Bifunctional alkylating agents form interstrand cross-links (ICLs) which are more complex and highly cytotoxic. ICLs are repaired by complex of NER factors (e.g., endnuclease xeroderma pigmentosum complementation group F-excision repair cross-complementing rodent repair deficiency complementation group 1), Fanconi anemia repair, and homologous recombination. A detailed understanding of how cells cope with DNA damage caused by alkylating agents is therefore potentially useful in clinical medicine.

Sevoflurane and isoflurane genotoxicity in kidney cells of mice

“…Another important fact, which has to be mentioned, is that compound A may be an alkylating agent (4,17). This could explain why we observed an increase in damage levels using the alkaline comet assay at time points six and 24 h, considering that DNA lesions induced by the alkylating agents in general require the involvement of more complex repair systems (29,30), than the "simple" types of DNA damage as strand breaks or alkali labile sites, which are usually repaired within few hours after infliction.…”

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“…Nevertheless, the functional significance of BER in prevention, development and treatment of disease remains unclear. Kondo N., et al, 2010Kaina, B., et al, 2007 Homologous recombination (HR) and non-homologous end-joining repair (NHEJ) Double strand breaks Dudas andChovanec, 2004 Helleday et al, 2007 Table 1. The main DNA repair pathways and types of DNA damage repaired.…”

“…If O 6 MeG remains in one of the template strands the repair process will be repeated, creating a "futile repair loop". This loop will eventually result in toxic double-strand breaks leading to chromosomal aberrations, cell-cycle arrest or apoptosis (Bugni et al, 2009;Kaina et al, 2007;Kaina et al, 2010;Kondo et al, 2010). When both of these systems fail to repair, O 6 MeG results in point mutations that can possibly initiate the carcinogenic process.…”