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

Mol Cell. 2004 Apr 9;14(1):105-16. doi: 10.1016/s1097-2765(04)00162-5.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Apoptosis / physiology*
  • Arabidopsis Proteins / metabolism
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Base Pair Mismatch
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line
  • Cysteine Proteinase Inhibitors / metabolism
  • DNA Damage*
  • DNA Repair
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Fas Ligand Protein
  • Fatty Acid Desaturases / metabolism
  • Guanosine / analogs & derivatives*
  • Guanosine / metabolism*
  • Humans
  • Membrane Glycoproteins / metabolism
  • Methylnitronitrosoguanidine / metabolism
  • MutS DNA Mismatch-Binding Protein
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology*
  • bcl-X Protein
  • fas Receptor / metabolism

Substances

  • Arabidopsis Proteins
  • BCL2L1 protein, human
  • Bacterial Proteins
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • DNA-Binding Proteins
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • bcl-X Protein
  • fas Receptor
  • Guanosine
  • Methylnitronitrosoguanidine
  • 6'-O-methylguanosine
  • Fatty Acid Desaturases
  • Fad7 protein, Arabidopsis
  • Caspases
  • Adenosine Triphosphatases
  • MutS DNA Mismatch-Binding Protein