DNA fragmentation factor subunit beta (DFFB) (DFFB)

DNA fragmentation factor subunit beta (DFFB), commonly known as DFF40 or Caspase-activated deoxyribonuclease (CAD), is the catalytic component of the DNA fragmentation factor complex essential for the execution of apoptosis [1, 3]. In non-apoptotic cells, DFF40 is sequestered in an inactive state by its inhibitor, DFF45 (ICAD). Upon induction of apoptosis, executioner caspases such as caspase-3 cleave DFF45, allowing DFF40 to homodimerize, oligomerize, and translocate to the nucleus where it functions as a magnesium-dependent endonuclease [8, 10]. It specifically targets double-stranded DNA at internucleosomal linker regions, resulting in the characteristic DNA laddering and contributing to chromatin condensation [9, 11]. DFF40 is a significant focus in oncology research because its downregulation or mislocalization is associated with apoptosis resistance and genomic instability in various malignancies, including glioblastoma and renal cell carcinoma [7, 14]. Experimental therapeutic strategies involve using DFF40 as a potent cytotoxic payload in immunotoxins to selectively eliminate cancer cells [13]. However, challenges include the risk of genomic instability or the development of secondary cancers if DNA fragmentation is incomplete, as sublethal activation can lead to mutagenic translocations [12]. Additionally, the loss of DFF40 activity may facilitate the horizontal transfer of oncogenic DNA fragments to neighboring cells [12].

Other names

DFF40CADCaspase-activated deoxyribonucleaseCaspase-activated DNaseCaspase-activated nucleaseCPANDFF2DNA fragmentation factor 40 kDa subunit

DFF40 acts as a magnesium-dependent endonuclease that cleaves double-stranded DNA at internucleosomal linker regions during apoptosis [8, 10]. It is activated following the caspase-3-mediated cleavage of its inhibitor, DFF45 (ICAD) [8]. Experimental therapies utilize DFF40 as a cytotoxic payload in immunotoxins to induce targeted cell death in cancer cells [13]. Small molecules like acetazolamide can sensitize cells to apoptosis by promoting DFF40-mediated DNA fragmentation [15].