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.
展开▼
机译：烷基化剂的细胞毒性作用被细胞DNA修复过程大大减弱，因此需要对修复机制有清楚的了解。简单的甲基化剂会在N和O原子上形成加合物。 N-甲基化可通过碱基切除修复，AlkB同源物或核苷酸切除修复（NER）去除。 O 6 -甲基鸟嘌呤（MeG）最终会变成细胞毒性并致突变，可通过O 6 -甲基鸟嘌呤-DNA甲基转移酶和O 6 MeG：T错误配对可通过不匹配修复系统（MMR）识别。 MMR无法修复O 6 MeG / T错配，最终导致双链断裂。双官能烷基化剂形成链间交联（ICL），链间交联更复杂且具有高度细胞毒性。 ICLs可通过复杂的NER因子进行修复（例如，核酸内切酶干皮色素补充组F切除修复交叉互补啮齿动物修复缺陷补充组1），Fanconi贫血修复和同源重组。因此，对细胞如何应对烷基化剂引起的DNA损伤的详细了解可能在临床医学中有用。
展开▼
