Daxx

Telomere maintenance and elongation allows cells to gain replicative immortality and evade cellular senescence during cancer development. While most cancers use telomerase to maintain telomere lengths, a subset of cancers engage the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is present in 5%-10% of all cancers, although the prevalence is dramatically higher in certain cancer types, including complex karyotype sarcomas, isocitrate dehydrogenase-mutant astrocytoma (WHO grade II-IV), pancreatic neuroendocrine tumours, neuroblastoma and chromophobe hepatocellular carcinomas...

Human papillomavirus (HPV) E7 protein as an important viral factor was involved in the progression of cervical cancer by mediating the cellular signaling pathways. Daxx (Death domain-associated protein) can interact with a variety of proteins to affect the viral infection process. However, the interaction and its related function between HPV16 E7 and Daxx have not been adequately investigated. Here, it was found that HPV16 E7 can interact with Daxx in HeLa or C33A cells by co-immunoprecipitation. HPV16 E7 protein treatment can up-regulate Daxx protein expression, while the interference in Daxx expression and the agonists for JNK can both reduce the antagonistic effects of HPV16 E7 on TNF-α-induced apoptosis, suggesting that Daxx/JNK pathway may be involved in the anti-apoptotic activity of HPV16 E7...

Histone variant H3.3 differs from the canonical histone H3.1 by only five amino acids, yet its chaperone death domain-associated protein (DAXX) can specifically recognize H3.3 over H3.1, despite having a large DAXX-interacting surface on the H3.3-H4 heterodimer common to that on the H3.1-H4 complex. This observation gives rise to the question of, from the binding energy point view, how high binding specificity may be achieved with small differences of the overall binding energy for protein-protein interactions in general...

Chromatin is a crucial regulator of gene expression and tightly controls development across species. Mutations in only one copy of multiple histone genes were identified in children with developmental disorders characterized by microcephaly, but their mechanistic roles in development remain unclear. Here we focus on dominant mutations affecting histone H4 lysine 91. These H4K91 mutants form aberrant nuclear puncta at specific heterochromatin regions. Mechanistically, H4K91 mutants demonstrate enhanced binding to the histone variant H3...

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During fertilization, DAXX (death domain-associated protein) mediates histone variant H3.3 incorporation into heterochromatin, which plays an important role in the maintenance of genomic integrity. rDNA, the ribosomal gene, is included in the first wave of gene activation after fertilization. Our and other studies indicated that loss of Daxx disturbs rDNA heterochromatinization and promotes rDNA transcription without change in protein expression of H3.3. However, maternal and zygotic deletion of Daxx impairs blastocyst development...

Tumor cells need to activate a telomere maintenance mechanism, enabling limitless replication. The bulk of evidence supports that sarcomas predominantly use alternative lengthening of telomeres (ALT) mechanism, commonly associated with alterations in ATRX and DAXX. In our dataset, only 12.3% of sarcomas harbored alterations in these genes. Thus, we checked for the presence of other genomic determinants of high telomeric content in sarcomas. Our dataset consisted of 13555 sarcoma samples, sequenced as a part of routine clinical care on the FoundationOne®Heme platform...

Genomes comprise a large fraction of repetitive sequences folded into constitutive heterochromatin to protect genome integrity and cell identity. De novo formation of heterochromatin during preimplantation development is an essential step for preserving the ground-state of pluripotency and the self-renewal capacity of embryonic stem cells (ESCs). Yet, the molecular mechanisms responsible for the remodeling of constitutive heterochromatin are largely unknown. Here, we identify that DAXX, an H3.3 chaperone essential for the maintenance of ESCs in the ground state, accumulates in pericentromeric regions independently of DNA methylation...

Daxx functions as a histone chaperone for the histone H3 variant, H3.3, and is essential for embryonic development. Daxx interacts with Atrx to form a protein complex that deposits H3.3 into heterochromatic regions of the genome, including centromeres, telomeres, and repeat loci. To advance our understanding of histone chaperone activity in vivo, we developed two Daxx mutant alleles in the mouse germline, which abolish the interactions between Daxx and Atrx (DaxxY130A ), and Daxx and H3.3 (DaxxS226A ). We found that the interaction between Daxx and Atrx is dispensable for viability; mice are born at the expected Mendelian ratio and are fertile...

Multiple recurrent genetic and epigenetic aberrations have been associated with worse prognosis in multiple studies of neuroendocrine tumours (NETs), but these have been mainly small cohorts and univariate analysis. This review and meta-analysis will focus upon the literature available on NETs of the gastrointestinal (GI) tract, liver, biliary tract and pancreas. PubMed and Embase were searched for publications that investigated the prognostic value of (epi)genetic changes of neuroendocrine tumours. A meta-analysis was performed assessing the association of the (epi)genetic alterations with overall survival (OS), disease-free survival (DFS) or locoregional control (LRC)...

BACKGROUND: Necroptosis induced by receptor-interacting protein kinase 3 (RIPK3) is engaged in intracerebral hemorrhage (ICH) pathology. In this study, we explored the impact of RIPK3 activation on neuronal necroptosis and the mechanism of the death domain-associated protein (DAXX)-mediated nuclear necroptosis pathway after ICH. METHODS: Potential molecules linked to the progression of ICH were discovered using RNA sequencing. The level of DAXX was assessed by quantitative real-time PCR, ELISA, and western blotting...

Helicobacte r pylori ( H. pylori ) infection affects cell survival pathways, including apoptosis and proliferation in host cells, and disruption of this balance is the key event in the development of H. pylori -induced gastric cancer (HPGC). H. pylori infection induces alterations in microRNAs expression that may be involved in GC development. Bioinformatic analysis showed that microRNA-21 (miR-21) is significantly upregulated in HPGC. Furthermore, quantitative proteomics and in silico prediction were employed to identify potential targets of miR-21...

Heat shock protein 27 (Hsp27) is an important member of the chaperone protein family and its overexpression promotes cancer cell survival. Here, we investigated the apoptosis inducer role of the J2 compound (Hsp27 inhibitor) in human ovarian cancer cell lines (SKOV3 and OVCAR-3). Cell proliferation was measured by MTT assay. The parameters of J2-Hsp27 interaction were determined with molecular docking calculation. The inhibitory effect of the J2 compound on Hsp27 chaperone activity was investigated by luciferase activity assay...

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogenous behavior, whereby some small tumors are aggressive with a propensity for metastasis. Detection of somatic mutations associated with aggressive biology may help with patient stratification and surgical decision-making in patients with well-differentiated PanNETs. Using next-generation sequencing (NGS), we investigated the feasibility of detecting somatic mutations in endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA) specimens and determining the mutational concordance between the EUS-FNA specimens and the primary tumors...

Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases. In addition, all published RenNETs were systematically reviewed. Our cohort (4 men and 9 women, mean age 42, mean tumor size 7...

The presence and characteristics of HMTV in Iraqi breast cancer women are still unknown. Furthermore, the identification of HMTV in human breast carcinoma tissue of patients differs by country, and the factors that influence it are still unknown. In many epithelial tumor types, the EGFR and its signaling pathways outcomes are necessary for the behavior of cells and regulating their proliferation, and it has been discovered that DAXX has strong carcinogenic characteristics and could be a new treatment target...

BACKGROUND: Rectal neuroendocrine neoplasms (NENs) are rare neoplasms with limited understanding of its genomic alterations and molecular typing. METHODS: The paraffin-embedded tissue specimens of 38 patients with rectal NENs after surgery were subjected to whole gene sequencing (WGS), and mutation profilings were drawn to identify high-frequency mutation genes, copy-number variations (CNVs), tumor mutation burden (TMB), signal pathways, mutation signatures, DNA damage repair (DDR) genes, and molecular types...

Pancreatic neuroendocrine tumors (PanNETs) in familial tuberous sclerosis (TSC1 and TSC2 mutations) have been known and studied. However, little is known about PanNET patients harboring the very rare (less than 2%) sporadic TSC mutations. Some renal tumors have been shown to harbor sporadic TSC mutations, with a distinctive morphological correlate. We hereby describe this rather unusual molecular alteration in well-differentiated pancreatic neuroendocrine tumors (WD PanNETs) with a focus on their morphology and treatment outcomes...

Pancreatic neuroendocrine tumors (PanNETs) are a rare tumor entity with largely unpredictable progression and increasing incidence in developed countries. Molecular pathways involved in PanNETs development are still not elucidated, and specific biomarkers are missing. Moreover, the heterogeneity of PanNETs makes their treatment challenging and most approved targeted therapeutic options for PanNETs lack objective responses. Here, we applied a systems biology approach integrating dynamic modeling strategies, foreign classifier tailored approaches, and patient expression profiles to predict PanNETs progression as well as resistance mechanisms to clinically approved treatments such as the mammalian target of rapamycin complex 1 (mTORC1) inhibitors...

Promyelocytic leukemia Nuclear Bodies (PML NBs) are nuclear membrane-less organelles physically associated with chromatin underscoring their crucial role in genome function. The H3.3 histone chaperone complex HIRA accumulates in PML NBs upon senescence, viral infection or IFN-I treatment in primary cells. Yet, the molecular mechanisms of this partitioning and its function in regulating histone dynamics have remained elusive. By using specific approaches, we identify intermolecular SUMO-SIM interactions as an essential mechanism for HIRA recruitment in PML NBs...