DFFB

DFFB Background

DNA fragmentation factor subunit beta (DFFB) is one of the two subunits of the heterodimeric protein DNA Fragmentation Factor (DFF), a major endonuclease responsible for chromosomal DNA cleavage during apoptosis ^[1]. It is also called DNA fragmentation factor 40 kDa subunit (DFF40) because its molecular weight is 40 kDa. In non-apoptotic cells, DFF40 exists as a heterodimeric complex with DFF45. DFF40 is expressed and properly folded in the presence of DFF45, which acts as a molecular chaperone ^[1][2]. And DFF45 inhibits the DNase activity of DFF40. Upon activation of apoptosis, DFF45 is cleaved by caspase 3 and then dissociates from DFF40 ^[1][3], thus activating DFF40. So DFF40 is also known as caspase-activated DNase or nuclease (CAD or CPAN) ^[4]. DFF40 is an endonuclease specific for double-stranded DNA, but not single-stranded DNA or RNA. This introduces double-strand breaks but not single-strand nicks during its cleavage of chromatin ^[5][6]. Activated DFF40 can generate double-stranded breaks and cleaves chromosomal DNA into oligonucleosomal size fragments ^[7]. Its activity can be potentiated by high-mobility group proteins, as well as by histone H1 ^[8]. The biochemical hallmark of apoptosis is the cleavage of chromatin into nucleosomal fragments ^[9]. The related study reported that DFF40-deficient high-grade glioblastomas exhibited incomplete apoptosis, despite the correct activation of executioner caspases ^[10]. Bagheri et al. showed that DFF40 overexpression sensitized breast cancer cells to doxorubicin, suggesting that modulation of DFF40 levels may be a beneficial strategy for chemoresistant cancers' therapy ^[11]. However, the overexpression of exclusive DFF40 in nasopharyngeal carcinomas did not result in increased apoptosis of head and neck squamous carcinoma in response to oxidative stress because of the presence of DFF45 is mandatory for proper DFF40 folding ^[12].

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[2] Liu X, Li P, et al. DFF40 induces DNA fragmentation and chromatin condensation during apoptosis [J]. Proc Natl Acad Sci USA 1998; 95:8461–6.
[3] Sakahira H, Enari M, et al. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis [J]. Nature 1998; 391:96–9.
[4] Halenbeck R, MacDonald H, et al. CPAN, a human nuclease regulated by the caspase-sensitive inhibitor DFF45 [J]. Curr Biol 1998; 8:537–40.
[5] Liu, X., H. Zou, P. Widlak, et al. Activation of the apoptotic endonuclease DFF40 (caspaseactivated DNase or nuclease). Oligomerization and direct interaction with histone H1 [J]. J. Biol. Chem. 1999, 274: 13836–13840.
[6] Liu, X., P. Li, P. Widlak, et al. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis [J]. Proc. Natl. Acad. Sci. 1998, 95: 8461–8466.
[7] Liu X, Li P, et al. DFF40 induces DNA fragmentation and chromatin condensation during apoptosis [J]. Proc Natl Acad Sci USA 1998; 95:8461–6.
[8] Liu X, Zou H, et al. Activation of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease) [J]. J Biol Chem 1999; 74:13836–40.
[9] A.H Wyllie Glucocorticoid induced thymocyte apoptosis is associated with endogeneous endonuclease activation [J]. Nature, 284 (1980), pp. 555-556.
[10] Sánchez-Osuna M, Martínez-Escardó L, et al. An intrinsic DFF40/CAD endonuclease deficiency impairs oligonucleosomal DNA hydrolysis during caspase-dependent cell death: a common trait in human glioblastoma cells [J]. Neuro Oncol. 2016 Jul; 18(7):950-61.
[11] Bagheri F, Safarian S, et al. Sensitization of breast cancer cells to doxorubicin via stable cell line generation and overexpression of DFF40 [J]. Biochem Cell Biol. 2015 Dec; 93(6):604-10.
[12] Boon SS, Sim SP. Inhibitor of caspase-activated DNase expression enhances caspase-activated DNase expression and inhibits oxidative stress-induced chromosome breaks at the mixed lineage leukaemia gene in nasopharyngeal carcinoma cells [J]. Cancer Cell Int. 2015; 15():54.