CpG-specific common commitment in caspase-dependent and -independent cell deaths.
Cell death in mammals seems to have caspase-dependent and -independent pathways unlike that in Caenorhabditis elegans where CED-3 protease activation is the central command. A recent suggestion to define apoptosis as the caspase-dependent or caspase-committed cell death form and leave cell death committed by other pathways as just cell death was meant to categorize the apparent divergence in mammalian cell death pathways. However, we show CpG oligonucleotides (ODN) blocking caspase-dependent fas(CD95) ligand-mediated apoptosis as well as caspase-independent etoposide-mediated apoptosis and etoposide-zVAD-mediated necrosis. CpG specificity was demonstrated by reversing the CpG motif or replacing it with a methylated motif (mCpG) which failed to inhibit. CpG ODN blocked CpG-specific DNA cleavage by rare-cutting NotI restriction, which produced a megabase cleavage pattern similar to that in the fasL and etoposide cell death inductions. CpG ODN inhibition was similar to that by CpG-specific SssI methylase. A common CpG-specific commitment point preceding caspase-dependent and -independent cell death pathways was suggested. CpG-specific modulation is a key epigenetic mechanism in genomic imprinting, resisting nuclease restriction, and patterning of chromatin conformations. It is now shown to have a powerful effect modulating cell death.
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Department of Anatomy, Faculty of Medicine, National University of Singapore, Kent Ridge, 119260, Singapore.
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D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D018899:CpG Islands; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D009336:Necrosis; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009841:Oligonucleotides / Q000378:metabolism*; D010718:Phosphatidylserines / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D019384:Nucleic Acid Synthesis Inhibitors; D009841:Oligonucleotides; D010718:Phosphatidylserines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D005047:Etoposide; D020169:Caspases; D016650:Fluorescein-5-isothiocyanate