Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ataxia-telangiectasia (AT), a genetic disorder due to mutation of gene atm characterized by progressive neurological abnormalities in combination with oculocutaneous telangiectasias, immunodeficiency, and increased frequency of malignant formations, is inherited according to autosome recessive mechanism. Cells of the patients with AT show increased radio sensitivity and some markers of premature ageing. The telomere lengths are sharply shortened in these cells already from the birth. We studied radio sensitivity (at the dose 2 Gy) and manifestations of premature ageing markers in cultured skin fibroblasts obtained from two unrelated AT patients and their heterozygous parents. We have shown that all the markers studied, that is HP1-gamma, phosphorylation of the histone variant H2AX (gamma-H2AX), and focuses 53BP1, indicate premature ageing of both the patients' and their blood relatives' cells. However, cells of the heterozygous carriers express premature ageing to a less extent. Investigation of the repair process characteristics (the amount of gamma-H2AX and the deal of cells with focuses 53BP1 in their nuclei) after X-ray irradiation has given following results: the patients' cells complete repair only half even in 24 after irradiation, while the healthy donor's cells complete repair in 24 h. Heterozygous cells also reliably differ from healthy donor's cells. Only in the case of apoptosis marker, p21, heterozygous cells do not differ from normal cells, whereas the patients' cells differ significantly. It has been noted that the mutation of gene atm is related to suppression of DNA double-strand breaks (DSBs) repair systems, which, in its turn, is in accordance with the increased radio sensitivity and premature ageing at the cell level in the AT families.
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PMID:[Syndrome of premature ageing in ataxia-telangiectasia patients]. 1979 57

The histone chaperone nucleosome assembly protein, hNAP-1, is a host cofactor for the activity of the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. The interaction between these two proteins has been shown to be important for Tat-mediated transcriptional activation and for efficient viral infection. Visualization of HIV-1 transcription and fluorescence resonance energy transfer experiments performed in this work demonstrate that hNAP-1 is not recruited to the site of Tat activity but the two proteins interact at the nuclear rim. These data are consistent with a mechanism that requires hNAP-1 for the transport of Tat within the nucleus rather than for the remodeling of nucleosomes on the provirus. Protein-protein docking and molecular modeling of the complex suggest that this interaction occurs between the basic domain of Tat and the histone-binding domain. The combination of theoretical and whole cell studies provided new insights into the functional significance of the Tat:hNAP-1 recognition.
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PMID:Subcellular localization of the interaction between the human immunodeficiency virus transactivator Tat and the nucleosome assembly protein 1. 1988 48

Knowledge of protein domains that function as the biological effectors for diverse post-translational modifications of histones is critical for understanding how nuclear and epigenetic programs are established. Indeed, mutations of chromatin effector domains found within several proteins are associated with multiple human pathologies, including cancer and immunodeficiency syndromes. To date, relatively few effector domains have been identified in comparison to the number of modifications present on histone and non-histone proteins. Here we describe the generation and application of human modified peptide microarrays as a platform for high-throughput discovery of chromatin effectors and for epitope-specificity analysis of antibodies commonly utilized in chromatin research. Screening with a library containing a majority of the Royal Family domains present in the human proteome led to the discovery of TDRD7, JMJ2C, and MPP8 as three new modified histone-binding proteins. Thus, we propose that peptide microarray methodologies are a powerful new tool for elucidating molecular interactions at chromatin.
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PMID:Epigenome microarray platform for proteome-wide dissection of chromatin-signaling networks. 1995 76

The plant homeodomain (PHD) finger is found in many chromatin-remodeling proteins. This small approximately 65-residue domain functions as an "effector" that binds specific epigenetic marks on histone tails, recruiting transcription factors and nucleosome-associated complexes to chromatin. Mutations in the PHD finger or deletion of this domain are linked to a number of human diseases, including cancer, mental retardation, and immunodeficiency. PHD finger-containing proteins may become valuable diagnostic markers and targets to prevent and treat these disorders. In this review, we highlight the progress recently made in understanding the functional significance of chromatin targeting by mammalian PHD fingers, detail the molecular mechanisms and structural features of "histone code" recognition, and discuss the therapeutic potential of PHD fingers.
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PMID:PHD fingers: epigenetic effectors and potential drug targets. 2004 37

This paper provides an overview of computational de novo protein design methods, highlighting recent advances and successes. Four protein systems are described that are important targets for drug design: human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases. Target areas for drug design for each protein are described, along with known inhibitors, focusing on peptidic inhibitors, but also describing some small-molecule inhibitors. Computational design methods that have been employed in elucidating these inhibitors for each protein are outlined, along with steps that can be taken in order to apply computational protein design to a system that has mainly used experimental methods to date.
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PMID:Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases. 2021 Jul 52

Elucidating the mechanism of human immunodeficiency virus, type 1 (HIV-1) provirus transcriptional silencing in latently infected cells is crucial for understanding the pathophysiological process of HIV-1 infection. It is well established that hypoacetylation of histone proteins by histone deacetylases is involved in the maintenance of HIV-1 latency by repressing viral transcription. Although histone methylation is involved in the organization of chromatin domains and plays a central epigenetic role in gene expression, the role of histone methylation in the maintenance of HIV-1 latency has not been clarified. Here we present evidence that histone H3 Lys(9) (H3K9) methyltransferase G9a is responsible for transcriptional repression of HIV-1 by promoting repressive dimethylation at H3K9 and for the maintenance of viral latency. We observed that G9a significantly inhibited basal, as well as, the induced HIV-1 gene expression by tumor necrosis factor-alpha or Tat. Mutant G9a, however, lacking the SET domain responsible for the catalytic activity of histone methyltransferase, did not show such an effect. When G9a expression was knocked down by small interfering RNA, HIV-1 replication was augmented from cells transiently transfected with a full-length HIV-1 clone. Moreover, a specific inhibitor of G9a, BIX01294, could reactivate expression of HIV-1 from latently infected cells such as ACH-2 and OM10.1. Furthermore, chromatin immunoprecipitation assays revealed the presence of G9a and H3K9 dimethylation on nucleosome histones in the vicinity of the HIV-1 long terminal repeat promoter. These results suggest that G9a is responsible for the transcriptional quiescence of latent HIV-1 provirus and provide a molecular basis for understanding the mechanism by which HIV-1 latency is maintained.
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PMID:Involvement of histone H3 lysine 9 (H3K9) methyltransferase G9a in the maintenance of HIV-1 latency and its reactivation by BIX01294. 2223 90

Immunodeficiency, Centromeric region instability, Facial anomalies (ICF; OMIM #242860) syndrome, due to mutations in the DNMT3B gene, is characterized by inheritance of aberrant patterns of DNA methylation and heterochromatin defects. Patients show variable agammaglobulinemia and a reduced number of T cells, making them prone to infections and death before adulthood. Other variable symptoms include facial dysmorphism, growth and mental retardation. Despite the recent advances in identifying the dysregulated genes, the molecular mechanisms, which underlie the altered gene expression causing ICF phenotype complexity, are not well understood. Held the recently-shown tight correlation between epigenetics and microRNAs (miRNAs), we searched for miRNAs regulated by DNMT3B activity, comparing cell lines from ICF patients with those from healthy individuals. We observe that eighty-nine miRNAs, some of which involved in immune function, development and neurogenesis, are dysregulated in ICF (LCLs) compared to wild-type cells. Significant DNA hypomethylation of miRNA CpG islands was not observed in cases of miRNA up-regulation in ICF cells, suggesting a more subtle effect of DNMT3B deficiency on their regulation; however, a modification of histone marks, especially H3K27 and H3K4 trimethylation, and H4 acetylation, was observed concomitantly with changes in microRNA expression. Functional correlation between miRNA and mRNA expression of their targets allow us to suppose a regulation either at mRNA level or at protein level. These results provide a better understanding of how DNA methylation and histone code interact to regulate the class of microRNA genes and enable us to predict molecular events possibly contributing to ICF condition.
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PMID:Epigenetic alteration of microRNAs in DNMT3B-mutated patients of ICF syndrome. 2044 64

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder of childhood that is caused by mutations in the WAS gene. WAS encodes WASp, a protein that is known to function in the cytoplasm of hematopoietic cells and is required for the induced differentiation of CD4+ T helper type 1 (TH1) lymphocytes. Now, a paper in Science Translational Medicine describes another mechanism for impaired immunity in WAS by showing that WASp localizes in the nucleus and regulates histone modifications and chromatin structure, thereby modulating expression of the TH1 master gene TBX21 (TBET).
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PMID:Alternative control: what's WASp doing in the nucleus? 2057 67

The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (TH1) immunity alongside intact TH2 immunity. This suggests a role for WASp in patterning T(H) subtype immunity, yet the molecular basis for the TH1-TH2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the TH1 regulator gene TBX21 at the chromatin level. In primary TH1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a TH2 regulator gene) or RORc (a TH17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates TH1 cell fate choice in the human TH cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating TH1 cells. During TH1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASp-deficient TH cells, from natural mutation or RNA interference-mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under TH1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired TH1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a previously unappreciated role of WASp in the epigenetic control of T-BET transcription and provide a new mechanism for the pathogenesis of WAS by linking aberrant histone methylation at the TBX21 promoter to dysregulated adaptive immunity.
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PMID:Nuclear role of WASp in the pathogenesis of dysregulated TH1 immunity in human Wiskott-Aldrich syndrome. 2057 68

Pharmacological manipulations to purge human immunodeficiency virus (HIV) from latent reservoirs have been considered as an adjuvant therapeutic approach to highly-active antiretroviral therapy for the eradication of HIV. Our novel histone deacetylase inhibitor NCH-51 induced expression of latent HIV-1 with minimal cytotoxicity. Using chromatin immunoprecipitation assays, we observed a reduction of HDAC1 occupancy, histone hyperacetylation and the recruitment of positive transcription factors at the HIV-1 promoter in latently infected-cells under the treatment with NCH-51. Mutation studies of the long terminal repeat (LTR) revealed NCH-51 mediated gene expression through the Sp1 sites. When Sp1 expression was knocked-down by small interfering RNA, the NCH-51-mediated activation of a stably integrated HIV-1 LTR was attenuated. Moreover, the Sp1 inhibitor mithramycin A abolished the effects of NCH-51.
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PMID:Novel histone deacetylase inhibitor NCH-51 activates latent HIV-1 gene expression. 2140 72


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