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Regulation and action of the major apoptotic nucleases: DFF40/CAD and Endonuclease G
Author(s) -
Widlak Piotr,
Garrard William T
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a119-c
Subject(s) - apoptotic dna fragmentation , chromatin , nuclease , dna fragmentation , microbiology and biotechnology , icad , endonuclease , biology , apoptosis , fragmentation (computing) , protein subunit , dna , chemistry , biochemistry , programmed cell death , gene , ecology
One of the hallmarks of the terminal stages of apoptosis is DNA breakdown. Two major nucleases, termed DNA fragmentation factor (DFF) or caspase‐activated DNase (CAD) and endonuclease G (EndoG), are responsible for DNA fragmentation in apoptotic cells. Both endonucleases attack chromatin to yield 3′‐OH and 5′‐P residues, first at the level of 50–300 kb cleavage products and next at the level of internucleosomal DNA fragmentation, but these nucleases possess completely different cellular locations in normal cells and are regulated in vastly different ways. In non‐apoptotic cells, DFF exists in the nucleus as a heterodimer, composed of a 45 kD chaperone and inhibitor subunit (DFF45/ICAD) and a 40 kD latent nuclease subunit DFF40. Activation of caspase‐3 or −7 results in DFF45 cleavage and release of active DFF40 that forms homo‐oligomers. DFF40’s nuclease activity is further activated by histone H1, HMGB1/2 and topo II. DFF is regulated by multiple pre‐ and post‐activation fail‐safe steps, which include requirements during translation for DFF45 and Heat Shock Proteins to mediate appropriate folding to generate a potentially activatable nuclease, and the synthesis in stoichiometric excess of the inhibitor. By contrast, EndoG resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon disruption of mitochondrial membrane permeability. EndoG associates with co‐activators in the nucleus such as AIF or FEN‐1. Chromatin fragmentation induced by apoptotic nucleases triggers characteristic chromatin condensation, another hallmark of cells undergoing apoptosis. Research supported by NIH and the Robert A. Welch Foundation.