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death domain-associated protein 6; Daxx; hDaxx; ETS1-associated protein 1; EAP1; Fas death domain-associated protein (DAXX, BING2, DAP6)
Function:
- 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 & enhances the intrinsic E3 ligase activity of MDM2 towards TP53, thus promoting TP53 ubiquitination & subsequent proteasomal degradation
- upon DNA damage, its association with MDM2 & USP7 is disrupted, resulting in increased MDM2 autoubiquitination & MDM2 degradation, which leads to TP53 stabilization
- proposed to mediate activation of the JNK pathway & apoptosis via MAP3K5 in response to signaling from TNFRSF6 & TGFBR2
- interaction with HSPB1/HSP27 may prevent interaction with TNFRSF6 & MAP3K5 & block DAXX-mediated apoptosis
- in contrast, in lymphoid cells JNC activation & TNFRSF6- mediated apoptosis may not involve DAXX
- seems to regulate transcription in PML nuclear bodies together with PML & may influence TNFRSF6-dependent apoptosis
- down-regulates basal & activated transcription
- seems to act as a transcriptional corepressor & inhibits PAX3 & ETS1 through direct protein-protein interaction
- modulates PAX5 activity
- its transcription repressor activity is modulated by recruiting it to subnuclear compartments like the nucleolus or PML nuclear bodies through interactions with MCSR1 & PML, respectively
- sumoylated
- phosphorylated upon DNA damage, probably by ATM or ATR
- phosphorylated by HIPK1 upon glucose deprivation
- polyubiquitinated; which is promoted by CUL3 & SPOP & results in proteasomal degradation
- ubiquitinated by MDM2 inducing its degradation
- deubiquitinated by USP7; leading to stabilization
- homomultimer
- binds to the TNFRSF6 death domain via its C-terminus & to PAX5
- binds to SLC2A4/GLUT4, MAP3K5, TGFBR2, phosphorylated dimeric HSPB1/HSP27, CENPC1, ETS1, sumoylated PML, UBE2I & MCRS1
- part of a complex containing PAX5 & CREBBP
- interacts with HIPK2 & HIPK3 via its N-terminus
- interacts with HIPK1, which induces translocation from PML nuclear bodies to chromatin & enhances association with HDAC1
- the non-phosphorylated form binds to PAX3, PAX7, DEK, HDAC1, HDAC2, HDAC3, acetylated histone H4 & histones H2A, H2B, H3 & H4
- interacts with SPOP
- part of a complex consisting of DAXX, CUL3 & SPOP
- interacts with CBP; the interaction is dependent sumoylation of CBP & suppresses CBP transcriptional activity via recruitment of HDAC2 directly in the complex with TP53 & HIPK2
- interacts with AXIN1; the interaction stimulates interaction of DAXX with TP53
- stimulates Ser-46 phosphorylation of TP53
- induces cell death on UV irradiation
- interacts with HCMV tegument phosphoprotein pp71
- part of a complex with MDM2, DAXX, RASSF1 & USP7
- part of a complex with DAXX, MDM2 & USP7
- interacts (via N-terminus) with RASSF1 (via C-terminus); the interaction is independent of MDM2 & TP53
- interacts with MDM2; the interaction is direct
- interacts with USP7; the interaction is direct & independent of MDM2 & TP53
- interacts with TP53
Structure: belongs to the DAXX family
Compartment:
- cytoplasm, nucleus, nucleoplasm, PML nuclear body, nucleolus
- chromosome, centromere
- dispersed throughout the nucleoplasm, in PML nuclear bodies, & in nucleoli
- 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 nucleoplasm with accumulation in nuclear speckles
Alternative splicing: named isoforms=2
Expression:
- ubiquitous
- upon mitogenic stimulation by concanavalin-A
General
nuclear protein
phosphoprotein
pro apoptotic protein
Properties
SIZE: entity length = 740 aa
MW = 81 kD
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: Necessary for interaction with USP7 {1-160}
Ser phosphorylation site {S178}
coiled coil {180-217}
MOTIF: Ser phosphorylation site {S213}
Necessary for interaction with USP7 {347-570}
MOTIF: coiled coil {358-399}
nuclear translocation signal {391-395}
coiled coil {430-489}
acidic region {434-572}
MOTIF: acidic residue (SEVERAL)
Thr phosphorylation site {T459}
Ser phosphorylation site {S495}
MAP3K5 interaction {501-625}
SPOP interaction {626-740}
MOTIF: nuclear translocation signal {628-634}
Tyr phosphorylation site {Y648}
Ser phosphorylation site {S668}
Ser phosphorylation site {S671}
Ser phosphorylation site {S688}
Ser phosphorylation site {S690}
Ser phosphorylation site {S702}
Thr phosphorylation site {T709}
Ser phosphorylation site {S712}
Ser phosphorylation site {S737}
Ser phosphorylation site {S739}
Database Correlations
OMIM 603186
UniProt Q9UER7
Pfam PF03344
Entrez Gene 1616
Kegg hsa:1616
References
- UniProt :accession Q9UER7
- Atlas of Genetics & Cytogenetics in Oncology & Haematology
http://atlasgeneticsoncology.org//genes/DAXXID40265ch6p21.html