DNA damage induced by alkylating agents and repair pathways.
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). O(6)-methylguanine (MeG), which can eventually become cytotoxic and mutagenic, is repaired by O(6)-methylguanine-DNA methyltransferase, and O(6)MeG:T mispairs are recognized by the mismatch repair system (MMR). MMR cannot repair the O(6)MeG/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.
Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan.
Natsuko
N
Kondo
Akihisa
A
Takahashi
Koji
K
Ono
Takeo
T
Ohnishi