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Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the ''DAXX'' gene.


Function

Daxx, a Death domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death receptor Fas. It has been associated with
heterochromatin Heterochromatin is a tightly packed form of DNA or '' condensed DNA'', which comes in multiple varieties. These varieties lie on a continue between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role ...
and PML-NBs (Promyelocytic Leukaemia nuclear bodies) and has been implicated in many nuclear processes including transcription and cell cycle regulation. This gene encodes a multifunctional protein that resides in multiple locations in the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...
and in the cytoplasm. Daxx serves as an H3.3 specific histone chaperone, interacting with an H3.3/H4 dimer. It interacts with a wide variety of proteins, such as
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
antigen Fas, centromere protein C, and transcription factor erythroblastosis virus E26 oncogene homolog 1 ( ETS1). In the nucleus, the encoded protein functions as a potent transcription repressor that binds to sumoylated transcription factors. Its repression can be relieved by the sequestration of this protein into promyelocytic leukemia nuclear bodies or
nucleoli The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of sig ...
. This protein also associates with centromeres in
G2 phase G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the o ...
. In the cytoplasm, the encoded protein may function to regulate apoptosis. The subcellular localization and function of this protein are modulated by post-translational modifications, including
sumoylation In molecular biology, SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation (sometimes w ...
, phosphorylation and polyubiquitination.


Structure and localization

Daxx is uniformly expressed throughout the body, except in the testes and thymus, which have especially high expression of the protein. At the level of the cell, Daxx is found in the cytoplasm, interacting with Fas-receptor or other cytoplasmic molecules, as well as in the
nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...
, where it is interacting with some subnuclear structures. Several additional interacting proteins are known, but not always is there an understanding of the specific function and relevance of this interaction.


Nuclear

When the PML-NB are absent or disrupted, Daxx is delocalized and apoptosis does not occur. This interaction was demonstrated when PML-NB disrupted cells were treated and Daxx relocalized with the PML-NB. ATRX, a centromeric heterochromatin component co-localizes with Daxx. This partnership is found mainly in the S-phase of the cell cycle. No expression of Daxx leads to malfunction of S phase and cells with two nuclei are formed. Another centromeric component, CENP-C, associates with Daxx during interphase. While at first Daxx was said to be a "death protein", it is suggested that associating with centromeric components leads to another function of Daxx.


Cytoplasmic and membrane

Fas-receptor stimulation causes Daxx to translocate out of the nucleus and into the cytoplasm. The breakdown of glucose produces reactive oxygen species ( ROS). These induce extracellular Daxx to translocalize into the cytoplasm following an association with ASK1 (Apoptosis signal-regulating kinase1). Another mechanism for exogenous Daxx import involves CRM1. This transport mechanism is phosphorylation dependent. Nevertheless, it is not known whether the Fas-receptor stimuli or the ASK1 overexpression are caused by ROS or CRM1 mediated export.


Role in apoptosis


Fas-induced

After Fas stimulation, Daxx is activated and plays its role of pro-apoptotic protein in activating the c-JUN-N-Terminal Kinase ( JNK) pathway. This pathway normally regulates stress-induced cell death. It is also essential for development of nerval system by programmed cell death. The real apoptotic process starts after activating this pathway. Daxx does not activate JNK itself but rather the upstream JNK kinase kinase ASK1. Some kind of positive feedback system was also discovered; JNK activates HIPK2, which stands for the translocation of nuclear Daxx to the cytoplasm. In turn, Daxx activates ASK1.


TGF-β regulated

TGF-β regulates a variety of different cellular developmental processes including growth, differentiation, proliferation, and cell death. Daxx interacts with the TGF-β type II receptor by binding of C-terminal domain of the protein. When the cell is treated with TGF-β, HIPK2, a nuclear kinase, phosphorylates Daxx and the activated Daxx in turn activates the JNK pathway (see "The Daxx Pathway" figure).


Miscellaneous mechanisms

Glucose breakdown produces ROS, which leads to Daxx production and relocalization, activating JNK pathway in turn. Another inducer of Daxx production is the exposure to UV-radiation. ASK1 will be transported to the nucleus when UV-irradiation is used to treat the cell. It is still unknown as to whether ASK1 binds Daxx, due to UV-irradiation. Another important cell death-property of Daxx is the association with PML-NB. It was shown that Daxx associates with Pml only when exposed to high oxidative stress or UV-irradiation. Another study showed loss of Daxx pro-apoptotic function in case of a mutant without Pml.


Anti-apoptotic function

A rather surprising property of Daxx is its anti-apoptotic function. When Daxx was not expressed or disrupted during embryonic development, it resulted in an early stage lethality. Other studies showed that lack of Daxx gene caused a higher apoptotic rate in embryonic stem cells. Only when Daxx was bound to Pml were apoptosis rates higher, suggesting that associated cytoplasmic Daxx has the role of an anti-apoptotic molecule.


Other functions

The omnipresence of Daxx in the cell nucleus suggests that the protein may also function as a transcription factor. Although it contains no known DNA-binding domains, Daxx can interact and suppress several transcription factors, such as p53,
p73 p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized ...
, and NF-κB. Proteins other than transcription factors are also blocked or inhibited by Daxx, such as the TGF-β pathway regulator, Smad4, conferring upon Daxx a major role in TGF-β signaling.


References


Further reading

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External links

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PDBe-KB
provides an overview of all the structure information available in the PDB for Human Death domain-associated protein 6 {{Fas apoptosis signaling pathway