# DFFB

## Overview
DFFB, or DNA fragmentation factor subunit beta, is a gene that encodes the protein CAD (Caspase-Activated DNase), a crucial enzyme in the apoptotic pathway. This protein is primarily involved in the enzymatic degradation of DNA during programmed cell death, functioning within a heterodimeric complex alongside DFFA (DNA fragmentation factor subunit alpha), which regulates its activity. CAD is activated by caspase-3, which cleaves DFFA during apoptosis, allowing CAD to enter the nucleus and fragment DNA. This process is essential for the orderly disassembly and removal of cells, playing a vital role in maintaining tissue homeostasis and preventing pathological conditions associated with defective apoptosis (Lee2015Profiles; Judson2000Structure). CAD's function and its regulation are critical for its role in apoptosis, highlighting its importance in both normal cellular processes and various disease states where apoptosis is disrupted.

## Structure
The molecular structure of the DFFB protein, also known as CAD (Caspase-Activated DNase), includes several notable features that are critical for its function in DNA fragmentation during apoptosis. The protein is encoded by a gene consisting of multiple exons, with the amino acid sequence encoded by these exons predicted to fold into specific structural domains. Notably, the amino-terminal CIDE-N domain mediates the interaction between DFFA and DFFB, which is essential for the activation of the DNA fragmentation activity of DFFB (Eckhart2007Phylogenomics).

Additionally, a WGR domain, which is proposed to be involved in nucleic acid binding, is predicted in the central region of the protein. This domain is identified using the SMART algorithm, suggesting its role in the molecular function of DFFB (Eckhart2007Phylogenomics). Critical residues for catalytic activity and zinc ion binding, such as D259, H260, H307, K309, H312, C226, C235, H239, and C306, are conserved across species, indicating the evolutionary conservation of these functional sites (Eckhart2007Phylogenomics).

The structure of DFFB is crucial for its role in the enzymatic degradation of nuclear DNA during apoptosis, with specific domains and conserved residues playing significant roles in its catalytic activity and interaction with other proteins in the apoptotic pathway.

## Function
In healthy human cells, the DFFB gene encodes the DNA fragmentation factor subunit beta, also known as CAD (Caspase-Activated DNase), which plays a crucial role in the process of apoptosis. DFFB/CAD is part of a heterodimeric complex with DFFA/ICAD, where DFFA/ICAD acts as an inhibitor and chaperone, regulating the activity of DFFB/CAD by preventing its premature action (Lee2015Profiles). This regulation ensures that DNA fragmentation, a hallmark of apoptosis, does not occur in healthy cells, thereby maintaining cellular integrity and preventing unwarranted cell death.

The activation of DFFB/CAD is tightly controlled by caspase-3, a key enzyme in the apoptotic pathway. During apoptosis, caspase-3 cleaves ICAD/DFF45, releasing DFFB/CAD to enter the nucleus and mediate the fragmentation of DNA. This process is essential for the orderly disassembly of cells, contributing to tissue homeostasis and the removal of cells that are no longer needed or are potentially harmful (Sertel2012Pharmacogenomic; Judson2000Structure).

Overall, DFFB/CAD is crucial for the controlled degradation of DNA during apoptosis, ensuring that the process is contained within the dying cell and does not harm neighboring cells or elicit an inflammatory response (Sertel2012Pharmacogenomic).

## Clinical Significance
DFFB (DNA fragmentation factor subunit beta), also known as CAD, plays a significant role in the pathogenesis of various cancers due to its function in apoptosis. In oligodendrogliomas, particularly those with 1p-allelic loss, DFFB is differentially expressed, suggesting its role as a tumor suppressor gene. The decreased expression of DFFB in these tumors, rather than mutations in the coding region, might contribute to tumorigenesis by exposing cells to DNA damage stresses, potentially influencing the response to DNA damaging chemotherapy (McDonald2005Attenuated). 

In neuroblastoma and Merkel cell carcinoma, DFFB has been investigated for mutations and its structural organization to understand its potential role as a tumor suppressor gene. Although specific mutations were not identified in the studies, the structural analysis and mutation screening in various cell lines and tumor samples highlight its clinical significance in these cancers (Judson2000Structure).

Furthermore, DFFB has been implicated in endometrial cancer, with identified mutation sites suggesting its involvement in the molecular mechanisms underlying this cancer type. This supports the potential of DFFB as a biomarker for sporadic and Lynch syndrome-related endometrial cancer (Gao2020HNRNPCL1PC).

## Interactions
DFFB, also known as DNA fragmentation factor subunit beta or CAD, is a key player in the apoptosis pathway, primarily involved in the fragmentation of DNA. It forms a complex with DFFA (DNA fragmentation factor subunit alpha), which acts as an inhibitor and a chaperone, preventing DFFB's nuclease activity until cleaved by caspase-3 during apoptosis (Eckhart2007Phylogenomics). Upon apoptotic stimuli, caspase-3 cleaves DFFA, releasing DFFB to form a homo-oligomer that binds and cleaves chromosomal DNA, a crucial step in programmed cell death (Larsen2016The).

DFFB interacts with various proteins that either enhance or inhibit its nucleolytic activity. For instance, histone H1 directly binds to DFFB, enhancing its DNA-binding capability, while the nucleophosmin/B23-PI3P complex and phosphorylated Ebp1-Akt complex bind to activated DFFB, inhibiting its nuclease activity (Widlak2008Roles). Additionally, DFFB is part of a network of interactions with proteins involved in chromatin structure and apoptosis, including members of the histone cluster 1 H1 family and high mobility group box proteins (Gao2020HNRNPCL1PC). These interactions are essential for the regulation of DFFB's function and the progression of apoptosis.


## References


[1. (Larsen2016The) Brian D. Larsen and Claus S. Sørensen. The caspase‐activated <scp>dn</scp>ase: apoptosis and beyond. The FEBS Journal, 284(8):1160–1170, December 2016. URL: http://dx.doi.org/10.1111/febs.13970, doi:10.1111/febs.13970. (130 citations) 10.1111/febs.13970](https://doi.org/10.1111/febs.13970)

[2. (McDonald2005Attenuated) J Matthew McDonald, Valerie Dunmire, Ellen Taylor, Raymond Sawaya, Janet Bruner, Gregory N Fuller, Kenneth Aldape, and Wei Zhang. Attenuated expression of dffb is a hallmark of oligodendrogliomas with 1p-allelic loss. Molecular Cancer, September 2005. URL: http://dx.doi.org/10.1186/1476-4598-4-35, doi:10.1186/1476-4598-4-35. (55 citations) 10.1186/1476-4598-4-35](https://doi.org/10.1186/1476-4598-4-35)

[3. (Gao2020HNRNPCL1PC) Yuan Gao, Xiuping Zhang, Tian Wang, Ye Zhang, Qing-xuan Wang, and Yuanjing Hu. Hnrnpcl1, pramef1, cfap74, and dffb: common potential biomarkers for sporadic and suspected lynch syndrome endometrial cancer. Cancer Management and Research, 12:11231 - 11241, 2020. (4 citations) 10.2147/CMAR.S262421](https://doi.org/10.2147/CMAR.S262421)

[4. (Lee2015Profiles) Sukkyoung Lee, Ilson Whang, Qiang Wan, Chulhong Oh, Youngdeuk Lee, Yucheol Kim, Hyowon Kim, and Jehee Lee. Profiles of teleost dna fragmentation factor alpha and beta from rock bream (oplegnathus fasciatus): molecular characterization and genomic structure and gene expression in immune stress. Genes &amp; Genomics, 38(2):193–204, November 2015. URL: http://dx.doi.org/10.1007/s13258-015-0359-1, doi:10.1007/s13258-015-0359-1. (2 citations) 10.1007/s13258-015-0359-1](https://doi.org/10.1007/s13258-015-0359-1)

[5. (Judson2000Structure) Hannah Judson, Nadine van Roy, Lisa Strain, Jo Vandesompele, Mireille Van Gele, Frank Speleman, and David T. Bonthron. Structure and mutation analysis of the gene encoding dna fragmentation factor 40 (caspase-activated nuclease), a candidate neuroblastoma tumour suppressor gene. Human Genetics, 106(4):406–413, April 2000. URL: http://dx.doi.org/10.1007/s004390000257, doi:10.1007/s004390000257. (62 citations) 10.1007/s004390000257](https://doi.org/10.1007/s004390000257)

[6. (Sertel2012Pharmacogenomic) Serkan Sertel, Tolga Eichhorn, Judith Bauer, Kai Hock, Peter K. Plinkert, and Thomas Efferth. Pharmacogenomic determination of genes associated with sensitivity or resistance of tumor cells to curcumin and curcumin derivatives. The Journal of Nutritional Biochemistry, 23(8):875–884, August 2012. URL: http://dx.doi.org/10.1016/j.jnutbio.2011.04.012, doi:10.1016/j.jnutbio.2011.04.012. (25 citations) 10.1016/j.jnutbio.2011.04.012](https://doi.org/10.1016/j.jnutbio.2011.04.012)

[7. (Widlak2008Roles) P. Widlak and W. T. Garrard. Roles of the major apoptotic nuclease-dna fragmentation factor-in biology and disease. Cellular and Molecular Life Sciences, 66(2):263–274, September 2008. URL: http://dx.doi.org/10.1007/s00018-008-8472-9, doi:10.1007/s00018-008-8472-9. (98 citations) 10.1007/s00018-008-8472-9](https://doi.org/10.1007/s00018-008-8472-9)

[8. (Eckhart2007Phylogenomics) Leopold Eckhart, Heinz Fischer, and Erwin Tschachler. Phylogenomics of caspase-activated dna fragmentation factor. Biochemical and Biophysical Research Communications, 356(1):293–299, April 2007. URL: http://dx.doi.org/10.1016/j.bbrc.2007.02.122, doi:10.1016/j.bbrc.2007.02.122. (20 citations) 10.1016/j.bbrc.2007.02.122](https://doi.org/10.1016/j.bbrc.2007.02.122)