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  1. Article: Introduction of Dicistrovirus IRESs into UAS/SV40-polyA constructs results in premature polyadenylation and strong overexpression of the upstream ORF in

    Lidsky, Peter V / Dmitriev, Sergey E / Andino, Raul

    bioRxiv : the preprint server for biology

    2023  

    Abstract: To evaluate the properties of insect virus internal ribosomal entry sites (IRESs) for protein expression ... ...

    Abstract To evaluate the properties of insect virus internal ribosomal entry sites (IRESs) for protein expression in
    Language English
    Publishing date 2023-10-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.04.560905
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cell death or survival: Insights into the role of mRNA translational control.

    Bhatter, Nupur / Dmitriev, Sergey E / Ivanov, Pavel

    Seminars in cell & developmental biology

    2023  Volume 154, Issue Pt B, Page(s) 138–154

    Abstract: Cellular stress is an intrinsic part of cell physiology that underlines cell survival or death. The ability of mammalian cells to regulate global protein synthesis (aka translational control) represents a critical, yet underappreciated, layer of ... ...

    Abstract Cellular stress is an intrinsic part of cell physiology that underlines cell survival or death. The ability of mammalian cells to regulate global protein synthesis (aka translational control) represents a critical, yet underappreciated, layer of regulation during the stress response. Various cellular stress response pathways monitor conditions of cell growth and subsequently reshape the cellular translatome to optimize translational outputs. On the molecular level, such translational reprogramming involves an intricate network of interactions between translation machinery, RNA-binding proteins, mRNAs, and non-protein coding RNAs. In this review, we will discuss molecular mechanisms, signaling pathways, and targets of translational control that contribute to cellular adaptation to stress and to cell survival or death.
    MeSH term(s) Animals ; Protein Biosynthesis/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Cell Death ; Mammals/genetics
    Chemical Substances RNA, Messenger ; RNA-Binding Proteins
    Language English
    Publishing date 2023-06-23
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1312473-0
    ISSN 1096-3634 ; 1084-9521
    ISSN (online) 1096-3634
    ISSN 1084-9521
    DOI 10.1016/j.semcdb.2023.06.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: mRNA Targeting, Transport and Local Translation in Eukaryotic Cells: From the Classical View to a Diversity of New Concepts.

    Lashkevich, Kseniya A / Dmitriev, Sergey E

    Molecular biology

    2021  Volume 55, Issue 4, Page(s) 507–537

    Abstract: Spatial organization of protein biosynthesis in the eukaryotic cell has been studied for more than fifty years, thus many facts have already been included in textbooks. According to the classical view, mRNA transcripts encoding secreted and transmembrane ...

    Abstract Spatial organization of protein biosynthesis in the eukaryotic cell has been studied for more than fifty years, thus many facts have already been included in textbooks. According to the classical view, mRNA transcripts encoding secreted and transmembrane proteins are translated by ribosomes associated with endoplasmic reticulum membranes, while soluble cytoplasmic proteins are synthesized on free polysomes. However, in the last few years, new data has emerged, revealing selective translation of mRNA on mitochondria and plastids, in proximity to peroxisomes and endosomes, in various granules and at the cytoskeleton (actin network, vimentin intermediate filaments, microtubules and centrosomes). There are also long-standing debates about the possibility of protein synthesis in the nucleus. Localized translation can be determined by targeting signals in the synthesized protein, nucleotide sequences in the mRNA itself, or both. With RNA-binding proteins, many transcripts can be assembled into specific RNA condensates and form RNP particles, which may be transported by molecular motors to the sites of active translation, form granules and provoke liquid-liquid phase separation in the cytoplasm, both under normal conditions and during cell stress. The translation of some mRNAs occurs in specialized "translation factories," assemblysomes, transperons and other structures necessary for the correct folding of proteins, interaction with functional partners and formation of oligomeric complexes. Intracellular localization of mRNA has a significant impact on the efficiency of its translation and presumably determines its response to cellular stress. Compartmentalization of mRNAs and the translation machinery also plays an important role in viral infections. Many viruses provoke the formation of specific intracellular structures, virus factories, for the production of their proteins. Here we review the current concepts of the molecular mechanisms of transport, selective localization and local translation of cellular and viral mRNAs, their effects on protein targeting and topogenesis, and on the regulation of protein biosynthesis in different compartments of the eukaryotic cell. Special attention is paid to new systems biology approaches, providing new cues to the study of localized translation.
    Language English
    Publishing date 2021-05-30
    Publishing country Russia (Federation)
    Document type Journal Article
    ZDB-ID 213541-3
    ISSN 1608-3245 ; 0026-8933
    ISSN (online) 1608-3245
    ISSN 0026-8933
    DOI 10.1134/S0026893321030080
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: AgeMeta: Quantitative Gene Expression Database of Mammalian Aging.

    Tikhonov, Stanislav / Batin, Mikhail / Gladyshev, Vadim N / Dmitriev, Sergey E / Tyshkovskiy, Alexander

    Biochemistry. Biokhimiia

    2024  Volume 89, Issue 2, Page(s) 313–321

    Abstract: AgeMeta is a database that provides systemic and quantitative description of mammalian aging at the level of gene expression. It encompasses transcriptomic changes with age across various tissues of humans, mice, and rats, based on a comprehensive meta- ... ...

    Abstract AgeMeta is a database that provides systemic and quantitative description of mammalian aging at the level of gene expression. It encompasses transcriptomic changes with age across various tissues of humans, mice, and rats, based on a comprehensive meta-analysis of 122 publicly available gene expression datasets from 26 studies. AgeMeta provides an intuitive visual interface for quantification of aging-associated transcriptomics at the level of individual genes and functional groups of genes, allowing easy comparison among various species and tissues. Additionally, all the data in the database can be downloaded and analyzed independently. Overall, this work contributes to the understanding of the complex network of biological processes underlying mammalian aging and supports future advancements in this field. AgeMeta is freely available at: https://age-meta.com/.
    MeSH term(s) Rats ; Mice ; Humans ; Animals ; Gene Expression Profiling ; Transcriptome ; Aging/genetics ; Databases, Factual ; Mammals/genetics
    Language English
    Publishing date 2024-04-15
    Publishing country United States
    Document type Meta-Analysis ; Journal Article
    ZDB-ID 1109-5
    ISSN 1608-3040 ; 0006-2979 ; 0320-9717
    ISSN (online) 1608-3040
    ISSN 0006-2979 ; 0320-9717
    DOI 10.1134/S000629792402010X
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Monitoring integrated stress response in live

    Lidsky, Peter V / Yuan, Jing / Lashkevich, Kseniya A / Dmitriev, Sergey E / Andino, Raul

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Cells exhibit stress responses to various environmental changes. Among these responses, the integrated stress response (ISR) plays a pivotal role as a crucial stress signaling pathway. While extensive ISR research has been conducted on cultured cells, ... ...

    Abstract Cells exhibit stress responses to various environmental changes. Among these responses, the integrated stress response (ISR) plays a pivotal role as a crucial stress signaling pathway. While extensive ISR research has been conducted on cultured cells, our understanding of its implications in multicellular organisms remains limited, largely due to the constraints of current techniques that hinder our ability to track and manipulate the ISR in vivo. To overcome these limitations, we have successfully developed an internal ribosome entry site (IRES)-based fluorescent reporter system. This innovative reporter enables us to label Drosophila cells, within the context of a living organism, that exhibit eIF2 phosphorylation-dependent translational shutoff - a characteristic feature of the ISR and viral infections. Through this methodology, we have unveiled tissue- and cell-specific regulation of stress response in Drosophila flies and have even been able to detect stressed tissues in vivo during virus and bacterial infections. To further validate the specificity of our reporter, we have engineered ISR-null eIF2αS50A mutant flies for stress response analysis. Our results shed light on the tremendous potential of this technique for investigating a broad range of developmental, stress, and infection-related experimental conditions. Combining the reporter tool with ISR-null mutants establishes Drosophila as an exceptionally powerful model for studying the ISR in the context of multicellular organisms.
    Language English
    Publishing date 2023-07-14
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.07.13.548942
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Human Tissues Exhibit Diverse Composition of Translation Machinery.

    Anisimova, Aleksandra S / Kolyupanova, Natalia M / Makarova, Nadezhda E / Egorov, Artyom A / Kulakovskiy, Ivan V / Dmitriev, Sergey E

    International journal of molecular sciences

    2023  Volume 24, Issue 9

    Abstract: While protein synthesis is vital for the majority of cell types of the human body, diversely differentiated cells require specific translation regulation. This suggests the specialization of translation machinery across tissues and organs. Using ... ...

    Abstract While protein synthesis is vital for the majority of cell types of the human body, diversely differentiated cells require specific translation regulation. This suggests the specialization of translation machinery across tissues and organs. Using transcriptomic data from GTEx, FANTOM, and Gene Atlas, we systematically explored the abundance of transcripts encoding translation factors and aminoacyl-tRNA synthetases (ARSases) in human tissues. We revised a few known and identified several novel translation-related genes exhibiting strict tissue-specific expression. The proteins they encode include eEF1A1, eEF1A2, PABPC1L, PABPC3, eIF1B, eIF4E1B, eIF4ENIF1, and eIF5AL1. Furthermore, our analysis revealed a pervasive tissue-specific relative abundance of translation machinery components (e.g., PABP and eRF3 paralogs, eIF2B and eIF3 subunits, eIF5MPs, and some ARSases), suggesting presumptive variance in the composition of translation initiation, elongation, and termination complexes. These conclusions were largely confirmed by the analysis of proteomic data. Finally, we paid attention to sexual dimorphism in the repertoire of translation factors encoded in sex chromosomes (eIF1A, eIF2γ, and DDX3), and identified the testis and brain as organs with the most diverged expression of translation-associated genes.
    MeSH term(s) Humans ; Proteomics ; Amino Acyl-tRNA Synthetases ; Peptide Initiation Factors ; Peptide Elongation Factor 1
    Chemical Substances Amino Acyl-tRNA Synthetases (EC 6.1.1.-) ; Peptide Initiation Factors ; EEF1A2 protein, human ; Peptide Elongation Factor 1
    Language English
    Publishing date 2023-05-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24098361
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  7. Article ; Online: Functional Cyclization of Eukaryotic mRNAs.

    Alekhina, Olga M / Terenin, Ilya M / Dmitriev, Sergey E / Vassilenko, Konstantin S

    International journal of molecular sciences

    2020  Volume 21, Issue 5

    Abstract: The closed-loop model of eukaryotic translation states that mRNA is circularized by a chain of the cap-eIF4E-eIF4G-poly(A)-binding protein (PABP)-poly(A) interactions that brings 5' and 3' ends together. This circularization is thought to promote the ... ...

    Abstract The closed-loop model of eukaryotic translation states that mRNA is circularized by a chain of the cap-eIF4E-eIF4G-poly(A)-binding protein (PABP)-poly(A) interactions that brings 5' and 3' ends together. This circularization is thought to promote the engagement of terminating ribosomes to a new round of translation at the same mRNA molecule, thus enhancing protein synthesis. Despite the general acceptance and the elegance of the hypothesis, it has never been proved experimentally. Using continuous in situ monitoring of luciferase synthesis in a mammalian in vitro system, we show here that the rate of translation initiation at capped and polyadenylated reporter mRNAs increases after the time required for the first ribosomes to complete mRNA translation. Such acceleration strictly requires the presence of a poly(A)-tail and is abrogated by the addition of poly(A) RNA fragments or m
    MeSH term(s) 3' Untranslated Regions/genetics ; Animals ; Cell-Free System ; Cyclization ; Eukaryotic Initiation Factor-4E/chemistry ; Eukaryotic Initiation Factor-4E/genetics ; Eukaryotic Initiation Factor-4G/chemistry ; Eukaryotic Initiation Factor-4G/genetics ; Mice ; Peptide Chain Initiation, Translational/genetics ; Poly A/chemistry ; Poly A/genetics ; Protein Biosynthesis/genetics ; RNA Caps/chemistry ; RNA Caps/genetics ; RNA, Messenger/chemistry
    Chemical Substances 3' Untranslated Regions ; Eukaryotic Initiation Factor-4E ; Eukaryotic Initiation Factor-4G ; RNA Caps ; RNA, Messenger ; Poly A (24937-83-5)
    Language English
    Publishing date 2020-02-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21051677
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  8. Article ; Online: Crystal structure of the DENR-MCT-1 complex revealed zinc-binding site essential for heterodimer formation.

    Lomakin, Ivan B / Dmitriev, Sergey E / Steitz, Thomas A

    Proceedings of the National Academy of Sciences of the United States of America

    2018  Volume 116, Issue 2, Page(s) 528–533

    Abstract: The density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein support noncanonical translation initiation, promote translation reinitiation on a specific set of mRNAs with short upstream reading frames, and ... ...

    Abstract The density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein support noncanonical translation initiation, promote translation reinitiation on a specific set of mRNAs with short upstream reading frames, and regulate ribosome recycling. DENR and MCT-1 form a heterodimer, which binds to the ribosome. We determined the crystal structure of the heterodimer formed by human MCT-1 and the N-terminal domain of DENR at 2.0-Å resolution. The structure of the heterodimer reveals atomic details of the mechanism of DENR and MCT-1 interaction. Four conserved cysteine residues of DENR (C34, C37, C44, C53) form a classical tetrahedral zinc ion-binding site, which preserves the structure of the DENR's MCT-1-binding interface that is essential for the dimerization. Substitution of all four cysteines by alanine abolished a heterodimer formation. Our findings elucidate further the mechanism of regulation of DENR-MCT-1 activities in unconventional translation initiation, reinitiation, and recycling.
    MeSH term(s) Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Eukaryotic Initiation Factors/chemistry ; Eukaryotic Initiation Factors/genetics ; Eukaryotic Initiation Factors/metabolism ; Humans ; Oncogene Proteins/chemistry ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Protein Multimerization ; Protein Structure, Quaternary
    Chemical Substances Cell Cycle Proteins ; DENR protein, human ; Eukaryotic Initiation Factors ; MCTS1 protein, human ; Oncogene Proteins
    Language English
    Publishing date 2018-12-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1809688116
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  9. Article ; Online: Patterns of Aging Biomarkers, Mortality, and Damaging Mutations Illuminate the Beginning of Aging and Causes of Early-Life Mortality.

    Kinzina, Elvira D / Podolskiy, Dmitriy I / Dmitriev, Sergey E / Gladyshev, Vadim N

    Cell reports

    2019  Volume 29, Issue 13, Page(s) 4276–4284.e3

    Abstract: An increase in the probability of death has been a defining feature of aging, yet human perinatal mortality starts high and decreases with age. Previous evolutionary models suggested that organismal aging begins after the onset of reproduction. However, ... ...

    Abstract An increase in the probability of death has been a defining feature of aging, yet human perinatal mortality starts high and decreases with age. Previous evolutionary models suggested that organismal aging begins after the onset of reproduction. However, we find that mortality and incidence of diseases associated with aging follow a U-shaped curve with the minimum before puberty, whereas quantitative biomarkers of aging, including somatic mutations and DNA methylation, do not, revealing that aging starts early but is masked by early-life mortality. Moreover, our genetic analyses point to the contribution of damaging mutations to early mortality. We propose that mortality patterns are governed, in part, by negative selection against damaging mutations in early life, manifesting after the corresponding genes are first expressed. Deconvolution of mortality patterns suggests that deleterious changes rather than mortality are the defining characteristic of aging and that aging begins in very early life.
    MeSH term(s) Aging/genetics ; Aging/metabolism ; Animals ; Autistic Disorder/genetics ; Autistic Disorder/pathology ; Biological Evolution ; Biomarkers/metabolism ; DNA Methylation ; Embryo, Mammalian ; Genetic Predisposition to Disease ; Humans ; Infant, Newborn ; Mice ; Mice, Knockout ; Mutation ; Neoplasms/genetics ; Neoplasms/mortality ; Neoplasms/pathology ; Perinatal Mortality ; Reproduction/genetics ; Selection, Genetic ; Survival Analysis
    Chemical Substances Biomarkers
    Language English
    Publishing date 2019-12-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2019.11.091
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  10. Article ; Online: Relocalization of Translation Termination and Ribosome Recycling Factors to Stress Granules Coincides with Elevated Stop-Codon Readthrough and Reinitiation Rates upon Oxidative Stress.

    Makeeva, Desislava S / Riggs, Claire L / Burakov, Anton V / Ivanov, Pavel A / Kushchenko, Artem S / Bykov, Dmitri A / Popenko, Vladimir I / Prassolov, Vladimir S / Ivanov, Pavel V / Dmitriev, Sergey E

    Cells

    2023  Volume 12, Issue 2

    Abstract: Upon oxidative stress, mammalian cells rapidly reprogram their translation. This is accompanied by the formation of stress granules (SGs), cytoplasmic ribonucleoprotein condensates containing untranslated mRNA molecules, RNA-binding proteins, 40S ... ...

    Abstract Upon oxidative stress, mammalian cells rapidly reprogram their translation. This is accompanied by the formation of stress granules (SGs), cytoplasmic ribonucleoprotein condensates containing untranslated mRNA molecules, RNA-binding proteins, 40S ribosomal subunits, and a set of translation initiation factors. Here we show that arsenite-induced stress causes a dramatic increase in the stop-codon readthrough rate and significantly elevates translation reinitiation levels on uORF-containing and bicistronic mRNAs. We also report the recruitment of translation termination factors eRF1 and eRF3, as well as ribosome recycling and translation reinitiation factors ABCE1, eIF2D, MCT-1, and DENR to SGs upon arsenite treatment. Localization of these factors to SGs may contribute to a rapid resumption of mRNA translation after stress relief and SG disassembly. It may also suggest the presence of post-termination, recycling, or reinitiation complexes in SGs. This new layer of translational control under stress conditions, relying on the altered spatial distribution of translation factors between cellular compartments, is discussed.
    MeSH term(s) Animals ; Codon, Terminator ; Arsenites/pharmacology ; Arsenites/metabolism ; Ribosomes/metabolism ; Stress Granules ; Protein Biosynthesis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Oxidative Stress ; Mammals/metabolism
    Chemical Substances Codon, Terminator ; arsenite (N5509X556J) ; Arsenites ; RNA, Messenger
    Language English
    Publishing date 2023-01-08
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12020259
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