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1.
RNA Biol ; 17(4): 487-499, 2020 04.
Article in English | MEDLINE | ID: mdl-31944153

ABSTRACT

Y-box binding proteins are DNA- and RNA-binding proteins with an evolutionarily ancient and conserved cold shock domain. The Y-box binding protein 1 (YB-1) is the most studied due to its abundance in somatic cells. YB-1 is involved in a variety of cellular processes, including proliferation, differentiation and stress response. Here, using Ribo-Seq and RIP-Seq we confirm that YB-1 binds a wide range of mRNAs and globally acts as a translation inhibitor. Surprisingly, YBX1 knockout results in only minor alterations in the expression of other genes, mostly caused by changes in RNA abundance. But YB-3 mRNA is an exception: it is better translated in the absence of YB-1, thereby producing an increased amount of YB-3 and thus suggesting that its synthesis is under YB-1 negative control. We have shown that the set of mRNAs bound to YB-3 is strikingly similar to that of YB-1, and that the mRNA-binding by YB-3 is enhanced in the absence of YB-1, resulting in a similar global reduction of translation of bound mRNAs in YB-1-null cells. Thus, YB-3 acts as a substitute for YB-1 in mRNA binding and, probably, in global translational control.


Subject(s)
CCAAT-Enhancer-Binding Proteins/metabolism , Gene Expression Profiling/methods , Heat-Shock Proteins/metabolism , RNA, Messenger/metabolism , Y-Box-Binding Protein 1/metabolism , CCAAT-Enhancer-Binding Proteins/genetics , Gene Expression Regulation , Gene Knockout Techniques , HEK293 Cells , Heat-Shock Proteins/genetics , High-Throughput Nucleotide Sequencing , Humans , Protein Biosynthesis , RNA, Messenger/chemistry , Ribosomes/genetics , Ribosomes/metabolism , Y-Box-Binding Protein 1/genetics
2.
Mol Biol (Mosk) ; 52(3): 508-518, 2018.
Article in Russian | MEDLINE | ID: mdl-29989583

ABSTRACT

Pituitary tumor-transforming gene-1 (PTTG1) encodes securin, a multifunctional protein involved in development of various types of cancer. Securin participates in the regulation of sister chromatids separation and the expression of multiple genes involved in the control of the cell cycle, metabolism, and angiogenesis. In several human cell lines, we have found a novel short isoform of securin mRNA, which does not contain exons 3 and 4. After the translation of this new mRNA, a shortened protein is produced that, like the full-size form, is able to activate the transcription of cyclin D3 gene (CCND3), which controls the G1/S transition and angiogenesis factors VEGFA (vascular endothelial growth factor), and FGF2 (fibroblast growth factor 2) in HEK293 cells. However, unlike the full-size protein, the short isoform of PTTG1 does not affect the MYC gene expression because it lacks the DNA-binding domain, which is needed for its interactions with the MYC promoter. Furthermore, the short form of securin does not influence the expression of MYC transcriptional targets, such as TP53 and IL-8. Thus, we found a novel isoform of securin which is able to activate a more restricted repertoire of genes compared to the full-size protein.


Subject(s)
Cyclin D3/biosynthesis , Fibroblast Growth Factor 2/biosynthesis , Gene Expression Regulation, Neoplastic , Proto-Oncogene Proteins c-myc/biosynthesis , Securin/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Cyclin D3/genetics , Fibroblast Growth Factor 2/genetics , HEK293 Cells , Hep G2 Cells , Humans , Jurkat Cells , K562 Cells , MCF-7 Cells , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Proto-Oncogene Proteins c-myc/genetics , Securin/genetics , Vascular Endothelial Growth Factor A/genetics
3.
J Biomol Struct Dyn ; 36(1): 221-232, 2018 01.
Article in English | MEDLINE | ID: mdl-28024445

ABSTRACT

Structures of many metal-binding proteins are often obtained without structural cations in their apoprotein forms. Missing cation coordinates are usually updated from structural templates constructed from many holoprotein structures. Such templates usually do not include structural water, the important contributor to the ion binding energy. Structural templates are also inconvenient for taking into account structural modifications around the binding site at apo-/holo- transitions. An approach based upon statistical potentials readily takes into account structural modifications associated with binding as well as contribution of structural water molecules. Here, we construct a set of statistical potentials for Mg2+, Ca2+, and Zn2+ contacting with protein atoms of a different type or structural water oxygens. Each type of the cations tends to form tight contacts with protein atoms of specific types. Structural water contributes relatively more into the binding pseudo-energy of Mg2+ and Ca2+ than of Zn2+. We have developed PIONCA (Protein-Ion Calculator), a fast CUDA GPGPU-based algorithm that predicts ion-binding sites in apoproteins. Comparative tests demonstrate that PIONCA outperforms most of the tools based on structural templates or docking. Our software can be also used for locating bound cations in holoprotein structures with missing cation heteroatoms. PIONCA is equipped with an interactive web interface based upon JSmol.


Subject(s)
Apoproteins/chemistry , Cations/chemistry , Metals/chemistry , Water/chemistry , Algorithms , Apoproteins/metabolism , Binding Sites , Cations/metabolism , Computational Biology/methods , Metals/metabolism , Protein Binding , Software , Thermodynamics
4.
Biochemistry (Mosc) ; 83(12): 1534-1542, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30878028

ABSTRACT

CD40 receptor is expressed on B lymphocytes and other professional antigen-presenting cells. The binding of CD40 to its ligand CD154 on the surface of T helper cells plays an important role in the activation of B lymphocytes required for production of antibodies, in particular, against autoantigens. Association of several single nucleotide polymorphisms (SNPs) located in the non-coding areas of human CD40 locus with the elevated risk of autoimmune diseases has been demonstrated. The most studied of these SNPs is rs4810485 located in the first intron of the CD40 gene. Expression of the CD40 gene in B lymphocytes of donors homozygous for the common allelic variant of this polymorphism (G) is higher than in B cells from donors carrying the minor (T) variant. We investigated the enhancer activity of this fragment of the CD40 locus in human B cell lines and showed that it is independent on the rs4810485 alleles. However, the minor allelic variants of the rs4810485-linked SNPs rs548231435 and rs115662534 were associated with a significant decrease in the activity of the CD40 promoter due to the impairments in the binding of EBF1 and STAT1 transcription factors, respectively.


Subject(s)
Alleles , Autoimmune Diseases/genetics , CD40 Antigens/genetics , Enhancer Elements, Genetic/genetics , Polymorphism, Single Nucleotide , STAT1 Transcription Factor/metabolism , Trans-Activators/metabolism , Base Sequence , Biomarkers/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/genetics , Genes, Reporter/genetics , Humans , Introns/genetics , Protein Binding
5.
Acta Naturae ; 9(3): 94-102, 2017.
Article in English | MEDLINE | ID: mdl-29104781

ABSTRACT

The SLAMF1 gene encodes CD150, a transmembrane glycoprotein expressed on the surface of T and B-lymphocytes, NK-cells, dendritic cells, and subpopulations of macrophages and basophils. We investigated the functional regulatory polymorphisms of the SLAMF1 locus associated with autoimmune processes, using bioinformatics and a mutational analysis of the regulatory elements overlapping with polymorphic positions. In the reporter gene assay in MP-1 and Raji B-cell lines, the enhancer activity of the regulatory region of the locus containing the rs3753381 polymorphism demonstrated a twofold increase upon the introduction of the rs3753381 minor variant (G → A) associated with myasthenia gravis. An analysis of the nucleotide context in the vicinity of rs3753381 revealed that the minor version of this polymorphism improves several binding sites for the transcription factors of FOX and NFAT, and RXR nuclear receptors. All mutations that disrupt any of these sites lead to a decrease in the enhancer activity both in MP1 and in Raji cells, and each of the two B-cell lines expresses a specific set of these factors. Thus, the minor variant of the rs3753381 polymorphism may contribute to the development of myasthenia gravis by modulating SLAMF1 expression, presumably in pathogenic B-lymphocytes.

6.
Metallomics ; 9(2): 175-182, 2017 02 22.
Article in English | MEDLINE | ID: mdl-28128390

ABSTRACT

Adaptation of S. cerevisiae to toxic concentrations of manganese provides a physiological model of heavy metal homeostasis. Transcriptome analysis of adapted yeast cells reveals upregulation of cell wall and plasma membrane proteins including membrane transporters. The gene expression in adapted cells differs from that of cells under short-term toxic metal stress. Among the most significantly upregulated genes are PMA2, encoding an ortholog of Pma1 H+-ATPase of the plasma membrane, and YBR056W-A, encoding a putative membrane protein Mnc1 that belongs to the CYSTM family and presumably chelates manganese at the cell surface. We demonstrate that these genes are essential for the adaptation to toxic manganese concentration and propose an extended scheme of manganese detoxification in yeast.


Subject(s)
Adaptation, Physiological/drug effects , Manganese/toxicity , Proton-Translocating ATPases/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Transcriptome/drug effects , Cell Membrane/metabolism , Proton-Translocating ATPases/genetics , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics
7.
Bioinformatics ; 27(19): 2621-4, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21852305

ABSTRACT

MOTIVATION: Modern experimental methods provide substantial information on protein-DNA recognition. Studying arrangements of transcription factor binding sites (TFBSs) of interacting transcription factors (TFs) advances understanding of the transcription regulatory code. RESULTS: We constructed binding motifs for TFs forming a complex with HIF-1α at the erythropoietin 3(')-enhancer. Corresponding TFBSs were predicted in the segments around transcription start sites (TSSs) of all human genes. Using the genome-wide set of regulatory regions, we observed several strongly preferred distances between hypoxia-responsive element (HRE) and binding sites of a particular cofactor protein. The set of preferred distances was called as a preferred pair distance template (PPDT). PPDT dramatically depended on the TF and orientation of its binding sites relative to HRE. PPDT evaluated from the genome-wide set of regulatory sequences was used to detect significant PPDT-consistent binding site pairs in regulatory regions of hypoxia-responsive genes. We believe PPDT can help to reveal the layout of eukaryotic regulatory segments. CONTACT: ivan.kulakovskiy@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Subject(s)
Binding Sites/genetics , DNA/metabolism , Gene Expression Regulation/genetics , Regulatory Sequences, Nucleic Acid/genetics , Transcription Factors/metabolism , Amino Acid Motifs/genetics , Erythropoietin/genetics , Genome , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Nucleotide Motifs , Protein Binding/genetics , Proteins/genetics , Proteins/metabolism , Transcription Factors/genetics , Transcription Initiation Site
8.
Bioinformatics ; 26(20): 2622-3, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20736340

ABSTRACT

SUMMARY: ChIP-Seq data are a new challenge for motif discovery. Such a data typically consists of thousands of DNA segments with base-specific coverage values. We present a new version of our DNA motif discovery software ChIPMunk adapted for ChIP-Seq data. ChIPMunk is an iterative algorithm that combines greedy optimization with bootstrapping and uses coverage profiles as motif positional preferences. ChIPMunk does not require truncation of long DNA segments and it is practical for processing up to tens of thousands of data sequences. Comparison with traditional (MEME) or ChIP-Seq-oriented (HMS) motif discovery tools shows that ChIPMunk identifies the correct motifs with the same or better quality but works dramatically faster. AVAILABILITY AND IMPLEMENTATION: ChIPMunk is freely available within the ru_genetika Java package: http://line.imb.ac.ru/ChIPMunk. Web-based version is also available. CONTACT: ivan.kulakovskiy@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Subject(s)
Chromatin Immunoprecipitation/methods , Sequence Analysis, DNA/methods , Base Sequence , Binding Sites , DNA/chemistry , DNA/metabolism , Databases, Factual
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