DFFA

Official Full Name

DNA fragmentation factor subunit alpha

Organism

Homo sapiens

GeneID

1676

Background

Apoptosis is a cell death process that removes toxic and/or useless cells during mammalian development. The apoptotic process is accompanied by shrinkage and fragmentation of the cells and nuclei and degradation of the chromosomal DNA into nucleosomal units. DNA fragmentation factor (DFF) is a heterodimeric protein of 40-kD (DFFB) and 45-kD (DFFA) subunits. DFFA is the substrate for caspase-3 and triggers DNA fragmentation during apoptosis. DFF becomes activated when DFFA is cleaved by caspase-3. The cleaved fragments of DFFA dissociate from DFFB, the active component of DFF. DFFB has been found to trigger both DNA fragmentation and chromatin condensation during apoptosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

DFF1; ICAD; DFF-45;

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Detailed Information

Degradation of nuclear DNA by DNA fragmentation factors (DFF) is a critical step in mammalian apoptosis. Researchers used comparative genomics to determine the evolutionary history of the genes encoding the two DFF subunits DFFA (aka ICAD) and DFFB (CAD).

Discovery of DFFA

Direct homologues of DFFA and DFFB are found in Nematostella vectensis, a representative of the primitive metazoan vertebrates, as well as in a wide range of vertebrates and insects, but not in urochordates, echinoderms, or nematodes. The structural domain mediating the interaction of DFFA and DFFB, a caspase cleavage site in DFFA, and key amino acid residues for DFFB endonuclease activity are conserved in nematodes.

Structure and Function of DFFA

In flies, mice and human cells, the disassembly of apoptotic DNA involves the activity of the nuc-1 homologue DNaseII, but not before the DNA fragmentation factor (DFF), which consists of two substrates named DFFA/DFF45/ICAD and DFFB/DFF40/CAD that interact with each other through the amino-terminal CIDE-N structural domain. They interact with each other through the amino-terminal CIDE-N structural domain.

The mechanism of cell death in mammals is more complicated and consists of multiple ced-3 homologues, which make up the so-called caspase family of proteases, as well as a series of direct and indirect regulators of caspases.DFFA acts as a folding chaperone for DFFB, and inhibition of DFFA expression inhibits the expression of DFFB proteins. The combination of DFFA inhibits the enzymatically active DFFB in the complex, thus rendering DFF inactive in non-apoptotic cells. The activation of DFF is differentially regulated in mammals and flies. In mammalian cells, DFFA is cleaved at two sites by caspase-3, releasing active DFFB, whereas in flies, DFFA is cleaved at one site by a caspase and DFFB is cleaved by a caspase protein.

Relationship between DFFA and caspases

Apoptosis plays an important pathophysiological role in the homeostasis of the immune system. During apoptosis in vertebrates, DNA fragmentation factors (DFFs) have been shown to be essential for DNA fragmentation, and the resulting DNA fragments follow a ladder-like pattern. The retention of the caspase scission site in the I2 structural domain of DFFA suggests that caspase-mediated activation of nuclear DNA breakdown is an ancient evolutionary process. Indeed, a variety of caspase genes are present in the genomes of both the established model species and N. vectensis. A high degree of conservation was also found in the CIDE-N structural domains of DFFA and DFFB, as well as in the loci involved in the catalytic activity of DFFB. The fact that no species has only one DFF component confirms the concept that these proteins are interdependent for proper functioning.

References:

Eckhart L, Fischer H, Tschachler E. Phylogenomics of caspase-activated DNA fragmentation factor. Biochem Biophys Res Commun. 2007;356(1):293-299. doi:10.1016/j.bbrc.2007.02.122
Xiang Z, Qu F, Qi L, et al. Cloning and characterization of an apoptosis-related DNA fragmentation factor (DFF) from oyster, Crassostrea hongkongensis. Fish Shellfish Immunol. 2014;38(1):119-126. doi:10.1016/j.fsi.2014.03.006

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