Apoptotic signaling in response to a single type of DNA lesion, O6-methylguanine
Apoptotic signaling in response to a single type of DNA lesion, O6-methylguanine
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DOI：
10.1016/s1097-2765(04)00162-5
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发表时间：
2004-04-09
期刊：
影响因子：
16
通讯作者：
Samson, LD
中科院分区：
文献类型：
--
作者：
Hickman, MJ;Samson, LD
到目前为止，很难确切地确定特定的DNA损伤是如何发出凋亡信号的，因为每种DNA损伤剂都会产生一系列不同的DNA损伤，并对RNA、蛋白质和脂质产生损伤。我们已经在人类细胞中开发了一个系统，该系统专注于对单一类型的DNA损伤的反应，即O-6-甲基鸟嘌呤（O（6）MeG）。我们剖析了参与O（6）MeG诱导的细胞凋亡的信号通路，这种反应依赖于MutSalpha异源二聚体，通常参与DNA错配修复。O（6）MeG触发与死亡受体和神经元介导的凋亡相关的半胱天冬酶的强烈激活。尽管如此，O（6）MeG/MutSalpha触发的细胞凋亡仅部分依赖于半胱天冬酶的激活;此外，它仅由线粒体信号传导介导，而完全不受死亡受体信号传导的影响。最后，虽然Bcl-2和Bcl-x（L），细胞调节凋亡的负调节因子，可以有效地阻断O（6）MeG/MutSalpha依赖的凋亡，但它们不能阻止细胞最终死亡。
Until now, it has been difficult to establish exactly how a specific DNA lesion signals apoptosis because each DNA damaging agent produces a collection of distinct DNA lesions and produces damage in RNA, protein, and lipids. We have developed a system in human cells that focuses on the response to a single type of DNA lesion, namely O-6-methylguanine (O(6)MeG). We dissect the signaling pathways involved in O(6)MeG-induced apoptosis, a response dependent on the MutSalpha heterodimer that is normally involved in DNA mismatch repair. O(6)MeG triggers robust activation of caspases associated with both death receptor- and mitochondrial-mediated apoptosis. Despite this, O(6)MeG/MutSalpha-triggered apoptosis is only partly dependent on caspase activation; moreover, it is mediated solely by mitochondrial signaling and not at all by death receptor signaling. Finally, while Bcl-2 and Bcl-x(L), negative regulators of mitochondrial-regulated apoptosis, could effectively block O(6)MeG/MutSalpha-dependent apoptosis, they were unable to prevent the cells from ultimately dying.