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Mol Cell. 2004 Apr 9;14(1):105-16.

Apoptotic signaling in response to a single type of DNA lesion, O(6)-methylguanine.

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Department of Biological Engineering and Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.


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.

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