Methylating Agents and DNA Repair Responses: Methylated Bases and Sources of Strand Breaks
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- 作者：Michael D. Wyatt ; Douglas L. Pittman
- 刊名：Chemical Research in Toxicology
- 出版年：2006
- 出版时间：December 2006
- 年：2006
- 卷：19
- 期：12
- 页码：1580 - 1594
- 全文大小：322K
- 年卷期：v.19,no.12(December 2006)
- ISSN：1520-5010
文摘
The chemical methylating agents methylmethane sulfonate (MMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) have been used for decades as classical DNA damaging agents. These agents havebeen utilized to uncover and explore pathways of DNA repair, DNA damage response, and mutagenesis.MMS and MNNG modify DNA by adding methyl groups to a number of nucleophilic sites on the DNAbases, although MNNG produces a greater percentage of O-methyl adducts. There has been substantialprogress elucidating direct reversal proteins that remove methyl groups and base excision repair (BER),which removes and replaces methylated bases. Direct reversal proteins and BER, thus, counteract thetoxic, mutagenic, and clastogenic effects of methylating agents. Despite recent progress, the complexityof DNA damage responses to methylating agents is still being discovered. In particular, there is growingunderstanding of pathways such as homologous recombination, lesion bypass, and mismatch repair thatreact when the response of direct reversal proteins and BER is insufficient. Furthermore, the importanceof proper balance within the steps in BER has been uncovered with the knowledge that DNA structuralintermediates during BER are deleterious. A number of issues complicate the elucidation of the downstreamresponses when direct reversal is insufficient or BER is imbalanced. These include inter-species differences,cell-type-specific differences within mammals and between cancer cell lines, and the type of methyldamage or BER intermediate encountered. MMS also carries a misleading reputation of being aradiomimetic, that is, capable of directly producing strand breaks. This review focuses on the DNAmethyl damage caused by MMS and MNNG for each site of potential methylation to summarize whatis known about the repair of such damage and the downstream responses and consequences if the damageis not repaired.