DAXX
Description
The DAXX (death domain associated protein) is a protein-coding gene located on chromosome 6.
Death-associated protein 6, also known as Daxx, is a protein that in humans is encoded by the DAXX gene. 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 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 and 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 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. This protein also associates with centromeres in the G2 phase. In the cytoplasm, the encoded protein may function to regulate apoptosis.
DAXX is a transcription corepressor that represses the transcriptional activity of several sumoylated transcription factors. It downregulates both basal and activated transcription. Its repressor activity is regulated by its localization within the nucleus. Interactions with MCSR1 and PML recruit DAXX to the nucleolus and PML/POD/ND10 nuclear bodies, respectively. DAXX seems to regulate transcription in PML/POD/ND10 nuclear bodies in conjunction with PML and may influence TNFRSF6-dependent apoptosis. DAXX inhibits the transcriptional activation of PAX3 and ETS1 through direct protein-protein interactions and modulates PAX5 activity, likely involving CREBBP. DAXX functions as an adapter protein in the MDM2-DAXX-USP7 complex, regulating the ubiquitination activity of the RING-finger E3 ligase MDM2. In non-stress conditions, DAXX, in association with the deubiquitinating USP7, prevents MDM2 self-ubiquitination and enhances the intrinsic E3 ligase activity of MDM2 towards TP53, promoting TP53 ubiquitination and subsequent proteasomal degradation. Upon DNA damage, DAXX dissociates from MDM2 and USP7, leading to increased MDM2 autoubiquitination, MDM2 degradation, and TP53 stabilization. DAXX acts as a histone chaperone that facilitates the deposition of histone H3.3 and is a targeting component of the chromatin remodeling complex ATRX:DAXX, which possesses ATP-dependent DNA translocase activity. This complex catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres, as well as the in vitro remodeling of H3.3-containing nucleosomes. DAXX does not affect the ATPase activity of ATRX but alleviates its transcription repression activity. Upon neuronal activation, DAXX associates with regulatory elements of specific immediate early genes, promoting the deposition of histone H3.3, which may contribute to the transcriptional induction of these genes. DAXX is required for the recruitment of histone H3.3:H4 dimers to PML-nuclear bodies (PML-NBs), a process independent of ATRX and facilitated by ASF1A. PML-NBs are thought to act as regulatory sites for the incorporation of newly synthesized histone H3.3 into chromatin. In cases of CENPA overexpression, as found in various tumors, DAXX is involved in the mislocalization of CENPA to chromosomes. This ectopic localization involves a heterotypic tetramer containing CENPA and histones H3.3 and H4, decreasing CTCF binding to chromatin. DAXX is proposed to mediate the activation of the JNK pathway and apoptosis via MAP3K5 in response to signaling from TNFRSF6 and TGFBR2. Interaction with HSPB1/HSP27 may prevent interaction with TNFRSF6 and MAP3K5, blocking DAXX-mediated apoptosis. However, in lymphoid cells, JNC activation and TNFRSF6-mediated apoptosis may not involve DAXX. DAXX exhibits restriction activity towards human cytomegalovirus (HCMV) and acts as a positive regulator of the heat shock transcription factor HSF1 activity during the stress protein response. {ECO:0000269|PubMed:12140263, ECO:0000269|PubMed:14990586, ECO:0000269|PubMed:15016915, ECO:0000269|PubMed:15364927, ECO:0000269|PubMed:16845383, ECO:0000269|PubMed:17081986, ECO:0000269|PubMed:17942542, ECO:0000269|PubMed:20504901, ECO:0000269|PubMed:20651253, ECO:0000269|PubMed:23222847, ECO:0000269|PubMed:24200965, ECO:0000269|PubMed:24530302}
DAXX is also known as BING2, DAP6, EAP1, SMIM40.
