DAXX

DAXX Background

Death domain-associated protein 6 (DAXX) is a highly conserved nuclear protein involved in apoptosis, transcriptional repression, and embryonic development. It possesses a Ser/Pro/Thr-rich domain, an acidic domain, a coiled-coil region, and two paired amphipathic helices ^[1]. Fas-receptor stimulation causes DAXX to translocate out of the nucleus and into the cytoplasm. DAXX combines with Fas to transmit a Fas-associated death domain (FADD)-independent apoptotic signal by activating Jun N-terminal kinase (JNK) ^[2]. DAXX also mediates UV-induced JNK activation and apoptosis ^[3]. Apoptosis signal-regulating kinase 1 (Ask1) can translocate DAXX to the cytoplasm. The binding of DAXX and Ask1 may relieve an intramolecular interaction between the amino- and carboxyl-termini of Ask1, activating its kinase activity ^[4][5]. This a mitogen-activated protein kinase kinase kinase subsequently activates JNK. The promotion of Ask1-mediated apoptosis through DAXX is in a kinase- and caspase-independent manner ^[6]. Targeted ablation in the mouse unveiled that DAXX is essential for embryonic development ^[7]. As a component of promyelocytic leukemia protein-nuclear bodies (PML-NBs), DAXX interacts with PML in the mediation of the antiviral defense ^[8][9]. And DAXX also functions as a transcriptional regulator possessing transcriptional repression activity and interacts directly with several transcription factors such as Pax3/5 and Smad4 (5, 6) ^[10][11]. Besides, Pascal Drane´ and Khalid Ouararhni et al. identified that DAXX serves as a chaperone taking part in the replication-independent deposition of H3.3, one of the best-studied histone variants which can replace the major species, H3.1 ^[12].

[1] Kiriakidou, M., D. A. Driscoll, et al. Cloning and expression of primate Daxx cDNAs and mapping of the human gene to chromosome 6p21.3 in the MHC region [J]. DNA Cell Biol. 1997, 16:1289-1298.
[2] Yang, X., R. Khosravi-Far, et al. Daxx, a novel Fas-binding protein that activates JNK and apoptosis [J]. Cell 1997, 89:1067-1076.
[3] Wu, S., H. N. Loke, and A. Rehemtulla. Ultraviolet radiation-induced apoptosis is mediated by Daxx [J]. Neoplasia 2002, 4:486-492.
[4] Chang, H. Y., H. Nishitoh, et al. Activation of apoptosis signal- regulating kinase 1 (ASK1) by the adapter protein daxx [J]. Science, 1998, 281:1860-1863.
[5] Ko, Y. G., Y. S. Kang, et al. Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm [J]. J. Biol. Chem. 2001, 276:39103-39106.
[6] Charette, S. J., H. Lambert, and J. Landry. 2001. A kinase-independent function of Ask1 in caspase-independent cell death [J]. J. Biol. Chem. 276:36071-4.
[7] Jennifer S Michaelson, Philip Leder. RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX [J]. J Cell Sci. 2003 Jan 15;116(Pt 2):345-52.
[8] Ullman A. J., Hearing P. Cellular proteins PML and Daxx mediate an innate antiviral defense antagonized by the adenovirus E4 ORF3 protein [J]. J. Virol. 2008, 82, 7325–7335.
[9] Saffert R. T., Kalejta R. F. Inactivating a cellular intrinsic immune defense mediated by Daxx is the mechanism through which the human cytomegalovirus pp71 protein stimulates viral immediate-early gene expression [J]. J. Virol. 2006, 80, 3863–3871.
[10] Lehembre F., Müller S., et al. Regulation of Pax3 transcriptional activity by SUMO-1-modified PML [J]. Oncogene 2001, 20, 1–9.
[11] Chang C. C., Lin D. Y., et al. Daxx mediates the small ubiquitin-like modifier-dependent transcriptional repression of Smad4 [J]. J. Biol. Chem. 2005, 280, 10164–10173.
[12] Pascal Drane´, Khalid Ouararhni, et al. The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3 [J]. Genes Dev. 2010 Jun 15; 24(12): 1253–1265.