Alkbh2 protects against lethality and mutation in primary mouse embryonic fibroblasts.
Alkbh2 protects against lethality and mutation in primary mouse embryonic fibroblasts.
复制标题
DOI：
10.1016/j.dnarep.2012.02.005
复制
发表时间：
2012-05-01
期刊：
影响因子：
3.8
通讯作者：
O'Connor, Timothy R.
中科院分区：
文献类型：
--
作者：
Nay, Stephanie L.;Lee, Dong-Hyun;Bates, Steven E.;O'Connor, Timothy R.
烷化剂修饰DNA和RNA形成加合物，破坏复制和转录，触发细胞周期检查点和/或启动细胞凋亡。如果不修复，一些损伤可能具有细胞毒性和/或致突变性。在大肠杆菌中，烷基化修复蛋白B（Alk B）通过主要消除1-甲基腺嘌呤和3-甲基胞嘧啶提供对烷基化剂的一种形式的抗性，从而增加存活并防止突变。为了研究哺乳动物AlkB同系物Alkbh 2和Alkbh 3的生物学作用，它们都具有与AlkB相似的酶活性，我们评估了在Alkbh 2或Alkbh 3基因中具有靶向缺失的原代大蓝小鼠胚胎成纤维细胞（MEF）的存活和诱变。与野生型对照细胞相比，Alkbh 2缺陷型和Alkbh 3缺陷型MEF对甲磺酸甲酯（MMS）诱导的细胞毒性的敏感性高约2倍。野生型、Alkbh 2 −/−和Alkbh 3 −/− MEFs的自发突变频率相似（平均为1.3×10−5）。然而，尽管MMS处理后两种突变MEF的存活率相似，但与野生型MEF相比，MMS处理后只有Alkbh 2缺陷型MEF显示突变频率的统计学显著增加。因此，尽管Alkbh 2和Alkbh 3都可以保护免受MMS诱导的细胞死亡，但只有Alkbh 2显示出在用这种外源性甲基化剂处理后MEF DNA免受突变的统计学显著保护。
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 ~2-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−/− and Alkbh3−/− MEFs (average-1.3×10−5). 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.
登录
查看更多内容
影响因子：
13.8
作者：
Begley, TJ;Samson, LD
通讯作者：
Samson, LD
影响因子：
5.6
作者：
Groth, Petra;Auslander, Simon;Helleday, Thomas
通讯作者：
Helleday, Thomas
影响因子：
5.3
作者：
Fu, Dragony;Brophy, Jennifer A. N.;Samson, Leona D.
通讯作者：
Samson, Leona D.
DOI：
10.1073/pnas.0403489101
发表时间：
2004-09-28
影响因子：
11.1
作者：
Delaney, JC;Essigmann, JM
通讯作者：
Essigmann, JM
DOI：
10.1007/bf00383004
发表时间：
1985-01-01
期刊：
MOLECULAR AND GENERAL GENETICS
影响因子：
--
作者：
KATAOKA, H;SEKIGUCHI, M
通讯作者：
SEKIGUCHI, M