O35613 (DAXX_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 117. History...
Names and origin
|Protein names||Recommended name:|
Death domain-associated protein 6
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||739 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Transcription corepressor known to repress transcriptional potential of several sumoylated transcription factors. Down-regulates basal and activated transcription. Its transcription repressor activity is modulated by recruiting it to subnuclear compartments like the nucleolus or PML/POD/ND10 nuclear bodies through interactions with MCSR1 and PML, respectively. Seems to regulate transcription in PML/POD/ND10 nuclear bodies together with PML and may influence TNFRSF6-dependent apoptosis thereby. Inhibits transcriptional activatiopn of PAX3 and ETS1 through direct protein-protein interactions. Modulates PAX5 activity; the function seems to involve CREBBP. Acts as an adapter protein in a MDM2-DAXX-USP7 complex by regulating the RING-finger E3 ligase MDM2 ubiquitination activity. Under non-stress condition, in association with the deubiquitinating USP7, prevents MDM2 self-ubiquitination and enhances the intrinsic E3 ligase activity of MDM2 towards TP53, thereby promoting TP53 ubiquitination and subsequent proteasomal degradation. Upon DNA damage, its association with MDM2 and USP7 is disrupted, resulting in increased MDM2 autoubiquitination and consequently, MDM2 degradation, which leads to TP53 stabilization. Acts as histone chaperone that facilitates deposition of histone H3.3. Acts as targeting component of the chromatin remodeling complex ATRX:DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres, and the in vitro remodeling of H3.3-containing nucleosomes. Does not affect the ATPase activity of ATRX but alleviates its transcription repression activity. Upopn neuronal activation asociates with regulatory elements of selected immediate early genes where it promotes deposition of histone H3.3 which may be linked to transcriptional induction of these genes. Required for the recruitment of histone H3.3:H4 dimers to PML-nuclear bodies (PML-NBs); the process is independent of ATRX and facilitated by ASF1A; PML-NBs are suggested to function as regulatory sites for the incorporation of newly synthesized histone H3.3 into chromatin. Proposed to mediate 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 and block DAXX-mediated apoptosis. In contrast, in lymphoid cells JNC activation and TNFRSF6-mediated apoptosis may not involve DAXX. Ref.3 Ref.9 Ref.10
Homomultimer. Interacts (via C-terminus) with TNFRSF6 (via death domain). Interacts with PAX5, SLC2A4/GLUT4, MAP3K5, TGFBR2, phosphorylated dimeric HSPB1/HSP27, CENPC, ETS1, sumoylated PML, UBE2I, MCRS1 and TP53. Interacts (via N-terminus) with HIPK2 and HIPK3. Interacts with HIPK1, which induces translocation from PML/POD/ND10 nuclear bodies to chromatin and enhances association with HDAC1. Interacts (non-phosphorylated) with PAX3, PAX7, DEK, HDAC1, HDAC2, HDAC3, acetylated histone H4 and histones H2A, H2B, H3, H3.3 and H4. Interacts with SPOP; mediating CUL3-dependent proteosomal degradation. Interacts with CBP; the interaction is dependent the sumoylation of CBP and suppresses CBP transcriptional activity via recruitment of HDAC2 directly in the complex with TP53 and HIPK2. Interacts with AXIN1; the interaction stimulates the interaction of DAXX with TP53, stimulates 'Ser-46' phosphorylation of TP53 on and induces cell death on UV irradiation. Interacts with MDM2; the interaction is direct. Interacts with USP7; the interaction is direct and independent of MDM2 and TP53. Part of a complex with DAXX, MDM2 and USP7 under non-stress conditions. Interacts (via N-terminus) with RASSF1 (via C-terminus); the interaction is independent of MDM2 and TP53; RASSF1 isoform Adisrupts interactions among MDM2, DAXX and USP7, thus contributing to the efficient activation of TP53 by promoting MDM2 self-ubiquitination in cell-cycle checkpoint control in response to DNA damage. Interacts with ATRX to form the chromatin remodeling complex ATRX:DAXX. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8
Cytoplasm. Nucleus › nucleoplasm. Nucleus › PML body. Nucleus › nucleolus By similarity. Note: Dispersed throughout the nucleoplasm, in PML/POD/ND10 nuclear bodies, and in nucleoli. Colocalizes with histone H3.3, ATRX, HIRA and ASF1A at PML-nuclear bodies. Colocalizes with a subset of interphase centromeres, but is absent from mitotic centromeres. Detected in cytoplasmic punctate structures. Translocates from the nucleus to the cytoplasm upon glucose deprivation or oxidative stress. Colocalizes with RASSF1 in the nucleus. Colocalizes with USP7 in nucleoplasma with accumulation in speckled structures. Colocalizes with histone H3.3, ATRX, HIRA and ASF1A at PML-nuclear bodies By similarity. Ref.3 Ref.10
Expressed as early as embryonic day 12.5 (E12. 5) in the neuroepithelium (ventricular zone). At E17.5, expression becomes more pronounced in postmitotic cells of the cortical plate (CP). Early postnatally (postnatal day 2 [P2]) and in the adult brain (P30) expressed both in the cortex and in the hippocampus. Ref.10
The Sumo interaction motif mediates Sumo binding, and is required both for sumoylation and binding to sumoylated targets By similarity.
Sumoylated with SUMO1 on multiple lysine residues By similarity.
Repressor activity is down-regulated upon Ser-669 phosphorylation. Upon neuronal activation dephosphorylated by calcineurin in a Ca2+ dependent manner at Ser-669; dephosphorylation positively affects histone H3.3 loading and transcriptional activation. Ref.6 Ref.10
Polyubiquitinated; which is promoted by CUL3 and SPOP and results in proteasomal degradation. Ubiquitinated by MDM2; inducing its degradation. Deubiquitinated by USP7; leading to stabilize it By similarity.
Belongs to the DAXX family.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 739||739||Death domain-associated protein 6||PRO_0000151259|
|Region||1 – 166||166||Necessary for interaction with USP7 and ATRX By similarity|
|Region||189 – 423||235||Interaction with histone H3.3 By similarity|
|Region||353 – 576||224||Necessary for interaction with USP7 By similarity|
|Region||626 – 739||114||Interaction with SPOP By similarity|
|Region||732 – 739||8||Sumo interaction motif (SIM) By similarity|
|Coiled coil||185 – 223||39||Potential|
|Coiled coil||364 – 403||40||Potential|
|Coiled coil||445 – 488||44||Potential|
|Motif||391 – 395||5||Nuclear localization signal Potential|
|Motif||622 – 628||7||Nuclear localization signal Potential|
|Compositional bias||11 – 16||6||Poly-Asp|
|Compositional bias||442 – 501||60||Asp/Glu-rich (acidic)|
Amino acid modifications
|Modified residue||219||1||Phosphoserine Ref.6|
|Modified residue||472||1||Phosphothreonine Ref.6|
|Modified residue||502||1||Phosphoserine Ref.6|
|Modified residue||515||1||Phosphoserine Ref.6|
|Modified residue||523||1||Phosphothreonine Ref.6|
|Modified residue||626||1||Phosphoserine Ref.6|
|Modified residue||669||1||Phosphoserine; by HIPK1 Ref.6 Ref.10|
|Modified residue||687||1||Phosphoserine By similarity|
|Modified residue||701||1||Phosphoserine By similarity|
|Modified residue||736||1||Phosphoserine By similarity|
|Modified residue||738||1||Phosphoserine By similarity|
|Cross-link||630||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity|
|Mutagenesis||502||1||S → A: No effect on phosphorylation by HIPK1. Ref.6|
|Mutagenesis||669||1||S → A: Diminishes phosphorylation by HIPK1. Ref.6|
|Sequence conflict||416||1||Q → K in AAC97971. Ref.2|
|Sequence conflict||452||1||D → DD in AAC97971. Ref.2|
|Sequence conflict||589||1||P → S in AAC97971. Ref.2|
|||"Daxx, a novel Fas-binding protein that activates JNK and apoptosis."|
Yang X., Khosravi-Far R., Chang H.Y., Baltimore D.
Cell 89:1067-1076(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"Sequence of the mouse major histocompatibility complex class II region."|
Rowen L., Qin S., Madan A., Loretz C., James R., Dors M., Mix L., Hall J., Lasky S., Hood L.
Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis."|
Zhong S., Salomoni P., Ronchetti S., Guo A., Ruggero D., Pandolfi P.P.
J. Exp. Med. 191:631-640(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PML.
|||"FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits Fas-mediated Jun NH2-terminal kinase activation."|
Rochat-Steiner V., Becker K., Micheau O., Schneider P., Burns K., Tschopp J.
J. Exp. Med. 192:1165-1174(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HIPK3.
|||"The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells."|
Emelyanov A.V., Kovac C.R., Sepulveda M.A., Birshtein B.K.
J. Biol. Chem. 277:11156-11164(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PAX5.
|||"Homeodomain-interacting protein kinase 1 modulates Daxx localization, phosphorylation, and transcriptional activity."|
Ecsedy J.A., Michaelson J.S., Leder P.
Mol. Cell. Biol. 23:950-960(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HIPK1, MUTAGENESIS OF SER-502 AND SER-669, PHOSPHORYLATION AT SER-219; THR-472; SER-502; SER-515; THR-523; SER-626 AND SER-669, IDENTIFICATION BY MASS SPECTROMETRY.
|||"SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx."|
Kuo H.-Y., Chang C.-C., Jeng J.-C., Hu H.-M., Lin D.-Y., Maul G.G., Kwok R.P.S., Shih H.-M.
Proc. Natl. Acad. Sci. U.S.A. 102:16973-16978(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CBP.
|||"The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3."|
Drane P., Ouararhni K., Depaux A., Shuaib M., Hamiche A.
Genes Dev. 24:1253-1265(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HISTONE H3.3.
|||"Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres."|
Lewis P.W., Elsaesser S.J., Noh K.M., Stadler S.C., Allis C.D.
Proc. Natl. Acad. Sci. U.S.A. 107:14075-14080(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS HISTONE CHAPERONE.
|||"Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation."|
Michod D., Bartesaghi S., Khelifi A., Bellodi C., Berliocchi L., Nicotera P., Salomoni P.
Neuron 74:122-135(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN HISTONE H3.3 DEPOSITION, SUBCELLULAR LOCATION, DEPHOSPHORYLATION AT SER-669 BY CALCINEURIN, DEVELOPMENTAL STAGE.
|+||Additional computationally mapped references.|
|AF006040 mRNA. Translation: AAC53284.1.|
AF110520 Genomic DNA. Translation: AAC97971.1.
AF100956 Genomic DNA. Translation: AAC69891.1.
|RefSeq||NP_001186662.1. NM_001199733.1. |
3D structure databases
|SMR||O35613. Positions 62-150, 188-392. |
Protein-protein interaction databases
|BioGrid||199054. 12 interactions.|
|IntAct||O35613. 14 interactions.|
Protocols and materials databases
Genome annotation databases
|MGI||MGI:1197015. Daxx. |
Gene expression databases
Family and domain databases
|InterPro||IPR005012. Daxx. |
|PANTHER||PTHR12766. PTHR12766. 1 hit. |
|Pfam||PF03344. Daxx. 1 hit. |
|Accession||Primary (citable) accession number: O35613|
Secondary accession number(s): Q9QWT8, Q9QWV3
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|