AlkB mystery solved: oxidative demethylation of N1-methyladenine and N3-methylcytosine adducts by a direct reversal mechanism
AlkB mystery solved: oxidative demethylation of N1-methyladenine and N3-methylcytosine adducts by a direct reversal mechanism
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DOI：
10.1016/s0968-0004(02)00010-5
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发表时间：
2003-01-01
影响因子：
13.8
通讯作者：
Samson, LD
中科院分区：
文献类型：
--
作者：
Begley, TJ;Samson, LD
所有生物体都有多种DNA修复途径，以防止烷基化诱导的突变和细胞死亡。近二十年来，我们已经知道大肠杆菌alkB基因产物可以保护细胞免受S（N）2-烷化剂的杀伤，可能是通过DNA修复。尽管进行了许多尝试，但不能将特定的DNA修复活性分配给AlKB。现在，生物学和生物化学的突破，加上硅蛋白结构的发现，已经揭示了一种新的直接逆转DNA修复机制，即由AlKB催化的N1-甲基腺嘌呤或N3-甲基胞嘧啶DNA损伤的氧化去甲基化。该反应发生在单链和双链DNA上，并且需要AlkB结合的非血红素Fe 2+、O-2和α-酮戊二酸盐来氧化有害的甲基。随后是琥珀酸、二氧化碳和甲醛的释放，以及DNA中未受损的A或C的恢复。
All organisms have multiple DNA repair pathways to protect against alkylation-induced mutation and cell death. For nearly two decades, we have known that the Escherichia coli alkB gene product protects against cell killing by S(N)2-alkylating agents, probably through DNA repair. Despite numerous attempts, a specific DNA repair activity could not be assigned to AlKB. Now, a breakthrough in biology and biochemistry, coupled with the discovery of an in silica protein structure, has uncovered a novel direct reversal DNA repair mechanism that is catalyzed by AlKB, namely the oxidative demethylation of N1-methyladenine or N3-methylcytosine DNA lesions. This reaction occurs on both single and double-stranded DNA, and requires AlkB-bound non-heme Fe2+, O-2 and alpha-ketogluterate to oxidize the offending methyl group. This is followed by the release of succinate, CO2 and formaldehyde, and the restoration of undamaged A or C in DNA.