Roles of the Major Apoptotic Nuclease-DNA Fragmentation Factor-in Biology and Disease

Abstract

It has now been more than ten years since the discovery of the major apoptotic nuclease, DNA fragmentation factor (DFF), also known as caspase-activated DNase (CAD). Here we review the recent literature that has uncovered new insight into DFF's regulation, and both its positive and negative roles in human disease. Cells from mice deficient in DFF still undergo apoptotic death without significant cell-autonomous DNA degradation. Their corpses' genomes are subsequently degraded by lysosomal DNase II after phagocytosis. However,DFF-deficient mice are more susceptible to cancer. Indeed, several different cancers in humans are associated with defects in DFF expression and it has been proposed that DFF is a p53-independent tumor suppressor. Negative aspects of DFF expression include contributing to susceptibility to acquire systemic lupus erythematosus, to chromosomal translocations that result in mixed lineage leukemias, and in the possible spreading of oncogenes and HIV due to horizontal gene transfer.

Chromatin Collapse during Caspase-dependent Apoptotic Cell Death Requires DNA Fragmentation Factor, 40-kDa Subunit-/Caspase-activated Deoxyribonuclease-mediated 3′-OH Single-strand DNA Breaks

“…Irrespective of these theoretical considerations, the detailed study of the molecular mechanisms con- trolling nuclear collapse/disassembly during caspase-dependent apoptosis should be of outstanding interest to comprehend how chromatin is being compacted inside the nucleus of a cell committed to die. The physiopathological relevance relies on the fact that accurate packaging of the DNA (fragmented or not) would potentially minimize the spreading of harmful genes, such as oncogenes or viral DNA, through horizontal gene transfer (68).…”

Parole terms for a killer

“…6 One key feature of this potent signal is the ability to activate the primary nuclease involved in disseminating extensive DNA strand breaks, termed caspase activated DNase or CAD. 7 DNA damage in the form of genomic fragmentation is a well characterized component of cell death or apoptosis. Although early stage DNA fragmentation is not an absolute requirement for all early stage forms of apoptotic cell death, these nuclear events are assumed to improve the efficiency of the process.…”

Escherichia coli STb toxin induces apoptosis in intestinal epithelial cell lines

“…STb induces DNA fragmentation DNA Fragmentation Factor (DFF) is a key endonuclease activated by caspase-3 during apoptosis responsible for the degradation of internucleosomal DNA [32] into fragments multiples of 180 to 200 bp [33]. The DNA extracted from HRT-18 and IEC-18 cells following treatment with STb revealed DNA laddering when migrated in agarose gel as observed with staurosporine, our positive control for apoptosis (Fig.…”