Daxx Represses Expression of a Subset of Antiapoptotic Genes Regulated by Nuclear Factor-κB

Abstract

Daxx is a nuclear protein that localizes to PML oncogenic domains, sensitizes cells to apoptosis, and functions as a transcriptional repressor. We found that Daxx represses the expression of several antiapoptotic genes regulated by nuclear factor-KB, including cIAP2, in human tumor cell lines. Daxx interacts with RelB and inhibits RelB-mediated transcriptional activation of the human cIAP2 gene promoter. Daxx also forms complexes with RelB while bound to its target sites in the cIAP2 promoter, as shown by electrophoretic mobility shift assays and chromatin immunoprecipitation experiments. Using cells from daxxÀ/À mouse embryos, we observed that levels of the corresponding murine c-IAP mRNA and protein are increased in cells lacking Daxx. Conversely, c-IAP mRNA and protein levels were reduced in relBÀ/À cells. Taken together, these observations provide a mechanism that links two previously ascribed functions of Daxx: transcriptional repression and sensitization to apoptosis. (Cancer Res 2006; 66(18): 9026-35)

Phosphorylation Drives an Apoptotic Protein to Activate Antiapoptotic Genes

“…PML nuclear bodies and their associated proteins such as PML, Sp100 (ND10-associated speckled, 100 kDa), Daxx, and ATRX (␣ thalassemia/mental retardation syndrome X-linked) as cellular defenses against viruses have been studied extensively (42)(43)(44)(45)(46)(47)(48)(49)(50). PML and Daxx associate with histone deacetylases, resulting in transcriptional repression (60), and Daxx recruits Dnmts to methylate and silence specific genes (38,39). Viral proteins of different viruses such as human cytomegalovirus, adenovirus, Epstein-Barr virus, human papillomavirus, avian sarcoma virus, Puumala virus, dengue virus, and phage C31 virus have been shown to interact with Daxx, resulting in either degradation or reorganization of Daxx to counteract its antiviral function for efficient viral replication (42,48).…”

“…Daxx lacks domains for sequence-dependent DNA binding (37), and it binds promoters through physical interaction with RelB (38,39), but during influenza A infection or in M1-overexpressing cells, promoter binding of Daxx was repressed (Fig. 3G).…”

“…RelB acts as both a transcriptional activator and a repressor of NF-B-dependent gene expression (29,30). However, death domain-associated protein 6 (Daxx), a histone chaperone (31)(32)(33) and transcription co-repressor (34 -37), inhibits RelB function by binding to it and recruiting DNA methyltransferase (Dnmt) family proteins, mainly Dnmt1 and Dnmt3a, that eventually methylate the promoters of the RelB-associated apoptosis inhibitory genes (38,39). Daxx is primarily located in the nucleus, often in a subnuclear compartment called nuclear domain 10 (ND10), promyelocytic leukemia (PML) nuclear bodies, or PML oncogenic domains (40,41).…”

“…1B). M1 protein has been shown to associate with PML nuclear body proteins (51,52), and Daxx has been shown to repress RelB (38,39). Thus, during early infection of influenza A (2-8 h.p.i.…”

The SUMO ligase PIAS1 regulates UV-induced apoptosis by recruiting Daxx to SUMOylated foci

“…Various lines of evidence suggest that Daxx can act as both a pro-and an antiapoptotic protein. Daxx is known to be involved in the axinmediated activation of p53 transcription, which leads to apoptosis (Li et al, 2007), and has been shown to suppress anti-apoptotic gene transcription by repressing NFkB transcriptional activity (Croxton et al, 2006). Conversely, RNAi-induced Daxx silencing has been shown to increase apoptosis (Michaelson and Leder, 2003) and sensitize cells to cellular stressors, such as UV and TNF-a (Tumor Necrosis Factor a) (Chen and Chen, 2003).…”