Alkbh2 protects against lethality and mutation in primary mouse embryonic fibroblasts

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• 作者：Stephanie L. Nay^a ; ^b ; Dong-Hyun Lee^b ; ^c ; ¹ ; Steven E. Bates^a ; ¹ ; Timothy R. O&rsquo ; Connor^a ; ^{toconnor@coh.org}
• 关键词：MMS ; methylmethane sulfonate ; ds ; double-stranded ; ss ; single-stranded ; ODN ; oligodeoxynucleotides ; 伪-KGFdiO ; 伪-ketoglutarate Fe(II) dioxygenase ; MEFs ; mouse embryonic fibroblasts ; mESCs ; mouse embryonic stem cells
• 刊名：DNA Repair
• 出版年：2012
• 期刊代码：121_15687864
• 类别：ch
• 出版时间：1 May, 2012
• 卷：11
• 期：5
• 页码：502-510
• 文件大小：1038 K

摘要

Alkylating agents modify DNA and RNA forming adducts that disrupt replication and transcription, trigger cell cycle checkpoints and/or initiate apoptosis. If left unrepaired, some of the damage can be cytotoxic and/or mutagenic. In Escherichia coli, the alkylation repair protein B (AlkB) provides one form of resistance to alkylating agents by eliminating mainly 1-methyladenine and 3-methylcytosine, thereby increasing survival and preventing mutation. To examine the biological role of the mammalian AlkB homologs Alkbh2 and Alkbh3, which both have similar enzymatic activities to that of AlkB, we evaluated the survival and mutagenesis of primary Big Blue mouse embryonic fibroblasts (MEFs) that had targeted deletions in the Alkbh2 or Alkbh3 genes. Both Alkbh2- and Alkbh3-deficient MEFs were 鈭?-fold more sensitive to methyl methanesulfonate (MMS) induced cytotoxicity compared to the wild type control cells. Spontaneous mutant frequencies were similar for the wild type, Alkbh2^鈭?鈭?/em> and Alkbh3^鈭?鈭?/em> MEFs (average - 1.3 脳 10^鈭?). However, despite the similar survival of the two mutant MEFs after MMS treatment, only the Alkbh2-deficient MEFs showed a statistically significant increase in mutant frequency compared to wild type MEFs after MMS treatment. Therefore, although both Alkbh2 and Alkbh3 can protect against MMS-induced cell death, only Alkbh2 shows statistically significant protection of MEF DNA against mutations following treatment with this exogenous methylating agent.