DNA Damage Induced by Alkylating Agents and Repair Pathways

Abstract EN

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.