Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents
Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents
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DOI：
10.1073/pnas.96.19.10764
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发表时间：
1999-09-14
影响因子：
11.1
通讯作者：
Samson, LD
中科院分区：
文献类型：
--
作者：
Hickman, MJ;Samson, LD
所有的细胞都暴露在化学物质中，这些化学物质可以使DNA烷基化，形成遗传毒性损伤。在形成的各种DNA损伤中，O-6-烷基鸟嘌呤损伤具有高度细胞毒性，我们最近证明O-6-甲基鸟嘌呤（O（6）MeG）和O-6-氯乙基鸟嘌呤（O（6）CEG）特异性地启动仓鼠细胞的凋亡。在这里，我们表明，在仓鼠和人类细胞中，DNA错配修复途径的MutS α分支（但不是MutS β分支）是绝对需要的信号启动细胞凋亡响应O（6）MeGs和部分需要信号细胞凋亡响应O（6）CEGs。此外，O（6）MeG损伤信号p53肿瘤抑制因子的稳定，这种信号也是MutS α依赖性的。尽管如此，MutS α依赖性细胞凋亡可以以p53非依赖性方式执行。DNA错配修复状态不影响细胞对p53和凋亡的其他诱导剂的反应。因此，似乎错配修复状态，而不是p53状态，是细胞对烷基化诱导的细胞凋亡的易感性的强指标。这个实验系统将允许解剖的信号转导事件，耦合特定类型的DNA碱基损伤与凋亡细胞死亡的最终结果。
All cells are unavoidably exposed to chemicals that can alkylate DNA to form genotoxic damage. Among the various DNA lesions formed, O-6-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O-6-methylguanine (O(6)MeG) and O-6-chloroethylguanine (O(6)CEG) specifically initiate apoptosis in hamster cells. Here we show, in both hamster and human cells, that the MutS alpha branch of the DNA mismatch repair pathway (but not the MutS beta branch) is absolutely required for signaling the initiation of apoptosis in response to O(6)MeGs and is partially required for signaling apoptosis in response to O(6)CEGs. Further, O(6)MeG lesions signal the stabilization of the p53 tumor suppressor, and such signaling is also MutS alpha-dependent. Despite this, MutS alpha-dependent apoptosis can be executed in a p53-independent manner. DNA mismatch repair status did not influence the response of cells to other inducers of p53 and apoptosis. Thus, it appears that mismatch repair status, rather than p53 status, is a strong indicator of the susceptibility of cells to alkylation-induced apoptosis. This experimental system will allow dissection of the signal transduction events that couple a specific type of DNA base lesion with the final outcome of apoptotic cell death.