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Your search keyword '"Warren, Alan [0000-0001-9277-4553]"' showing total 5 results
Start Over Author "Warren, Alan [0000-0001-9277-4553]" Topic biology
5 results on '"Warren, Alan [0000-0001-9277-4553]"'

1. A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit

Author

Leonor Miller-Fleming, Van Haute L, Rogan Jf, Adam M. Dinan, Andrew E. Firth, Alan J. Warren, Alexander J. Whitworth, Simone Pellegrino, Pedro Rebelo-Guiomar, Schraga Schwartz, Kyle Dent, Michal Minczuk, Sas Chen A, Caterina Garone, Byron Andrews, Rebelo-Guiomar, Pedro [0000-0002-5060-7519], Pellegrino, Simone [0000-0001-6302-2774], Van Haute, Lindsey [0000-0001-7809-1473], Dinan, Adam [0000-0003-2812-1616], Firth, Andrew [0000-0002-7986-9520], Whitworth, Alex [0000-0002-1154-6629], Warren, Alan [0000-0001-9277-4553], Minczuk, Michal [0000-0001-8242-1420], Apollo - University of Cambridge Repository, Firth, Andrew E [0000-0002-7986-9520], Whitworth, Alexander J [0000-0002-1154-6629], Warren, Alan J [0000-0001-9277-4553], Rebelo-Guiomar, Pedro, Pellegrino, Simone, Dent, Kyle C, Sas-Chen, Aldema, Miller-Fleming, Leonor, Garone, Caterina, Van Haute, Lindsey, Rogan, Jack F, Dinan, Adam, Firth, Andrew E, Andrews, Byron, Whitworth, Alexander J, Schwartz, Schraga, Warren, Alan J, and Minczuk, Michal

Subjects
Male, Mitochondrial translation, 631/535/1258/1259, Ribosome biogenesis, General Physics and Astronomy, 13, Transcriptome, Mitochondrial Ribosomes, Gene Knockout Techniques, HEK293 Cell, RNA, Ribosomal, 16S, Mitochondrial ribosome, Drosophila Proteins, Methyltransferase, 64, Multidisciplinary, 631/45/500, Gene Knockout Technique, article, Mitochondrial Ribosome, Cell biology, 64/24, Drosophila melanogaster, Essential gene, 38/77, Human, Ribosomal Proteins, 101, Protein subunit, 101/58, 631/337/1645, Biology, Methylation, General Biochemistry, Genetics and Molecular Biology, Ribosomal Protein, 38, 38/91, Animals, Humans, Animal, 101/28, RNA, General Chemistry, Methyltransferases, HEK293 Cells, Protein Biosynthesis, Drosophila Protein, 631/337/574/1789, Ribosome Subunits, Large, 631/80/642/333, Biogenesis
Abstract

Funder: Kay Kendall Leukaemia Fund (KKLF); doi: https://doi.org/10.13039/501100000402, Funder: EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011264; Grant(s): Mitobiopath-705560, Many cellular processes, including ribosome biogenesis, are regulated through post-transcriptional RNA modifications. Here, a genome-wide analysis of the human mitochondrial transcriptome shows that 2'-O-methylation is limited to residues of the mitoribosomal large subunit (mtLSU) 16S mt-rRNA, introduced by MRM1, MRM2 and MRM3, with the modifications installed by the latter two proteins being interdependent. MRM2 controls mitochondrial respiration by regulating mitoribosome biogenesis. In its absence, mtLSU particles (visualized by cryo-EM at the resolution of 2.6 ��) present disordered RNA domains, partial occupancy of bL36m and bound MALSU1:L0R8F8:mtACP anti-association module, allowing five mtLSU biogenesis intermediates with different intersubunit interface configurations to be placed along the assembly pathway. However, mitoribosome biogenesis does not depend on the methyltransferase activity of MRM2. Disruption of the MRM2 Drosophila melanogaster orthologue leads to mitochondria-related developmental arrest. This work identifies a key checkpoint during mtLSU assembly, essential to maintain mitochondrial homeostasis.

Published
2022

2. Somatic genetic rescue of a germline ribosome assembly defect

Author

Vasileios Kargas, Mélanie Parisot, Norberto Escudero-Urquijo, Alexis Bertrand, Christine Bellanné-Chantelot, Jean Donadieu, Mohammed Zarhrate, Patrick Nitschke, Cécile Masson, Laëtitia Kermasson, Beatriz Goyenechea, Sophie Kaltenbach, Alan J. Warren, David Traynor, Stefano Fumagalli, Li Jin, Blandine Beaupain, Bruno Reversade, Ahmed Z. Boukerrou, Peter J. Bond, M. Rossmann, Olivier Alibeu, Jean-Alain Martignoles, Christine Bole-Feysot, Jonathan Moreil, Shengjiang Tan, François Delhommeau, Patrick Revy, Kong Boo Phua, Alexandre Faille, Aurore Pouliet, Christine Hilcenko, Frédéric Tores, Isabelle Radford-Weiss, Ai Ling Koh, Isabelle Callebaut, Jean-Pierre de Villartay, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Laboratory of Molecular Biology [Cambridge, UK] (LMB), University of Cambridge [UK] (CAM)-Medical Research Council, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), KK Women's and Children's Hospital [Singapore], Genome Institute of Singapore (GIS), Bioinformatics Institute [Singapore], Agency for science, technology and research [Singapore] (A*STAR), National University of Singapore (NUS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Babraham Research Campus [Cambridge, Royaume-Uni], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Escudero-Urquijo, Norberto [0000-0002-8201-5884], Parisot, Mélanie [0000-0003-4312-2035], Reversade, Bruno [0000-0002-4070-7997], Bond, Peter J. [0000-0003-2900-098X], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J. [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Hilcenko, Christine [0000-0002-9596-7833], Rossmann, Maxim [0000-0001-8811-3277], Bond, Peter J [0000-0003-2900-098X], Warren, Alan [0000-0001-9277-4553], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), HAL-SU, Gestionnaire, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Warren, Alan J [0000-0001-9277-4553]

Subjects
Somatic cell, [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Germline, 631/208/737, 692/699/1541, Ribosome assembly, 13/1, 0302 clinical medicine, hemic and lymphatic diseases, 38/22, Dictyostelium, Eukaryotic Initiation Factors, Child, Cells, Cultured, Biological Phenomena, Genetics, 0303 health sciences, Multidisciplinary, 631/208/514/2254, article, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Ribosome Subunits, Large, Eukaryotic, Ribosome, Shwachman-Diamond Syndrome, 3. Good health, [SDV] Life Sciences [q-bio], 64/24, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Child, Preschool, Drosophila, Haematological diseases, Protein Binding, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Science, 45/23, Saccharomyces cerevisiae, Biology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, 82/80, 03 medical and health sciences, Young Adult, Germline mutation, Animals, Humans, Gene, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Sequence Homology, Amino Acid, Eukaryotic Large Ribosomal Subunit, Point mutation, Infant, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, SBDS, 96/44, Peptide Elongation Factors, Germ Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Protein Biosynthesis, Mutation, Next-generation sequencing, 631/337/574/1789, Ribosomes
Abstract

Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS., Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

Published
2021
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3. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome

Author

James S. Wainscoat, Luke R Holmes, Alison L Lane, Lesley F Drynan, Jillian L. Barlow, Silvia Lorenzo-Abalde, Alan J. Warren, Richard Pannell, See Heng Wong, Helen E. Jolin, Jacqueline Boultwood, Andrew N. J. McKenzie, Duncan R. Hewett, Angela J Middleton, Warren, Alan [0000-0001-9277-4553], and Apollo - University of Cambridge Repository

Subjects
Ribosomopathy, Apoptosis, Disease, Biology, Synteny, Genome, Article, General Biochemistry, Genetics and Molecular Biology, Mice, medicine, Animals, Humans, Anemia, Macrocytic, Genetics, Mechanism (biology), Myelodysplastic syndromes, Chromosome, General Medicine, Genes, p53, Hematopoietic Stem Cells, medicine.disease, Chromosomes, Mammalian, Disease Models, Animal, Myelodysplastic Syndromes, Immunology, Macrocytic anemia, Chromosome Deletion
Abstract

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome.

Published
2009
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4. Mechanism of eIF6 release from the nascent 60S ribosomal subunit

Author

David Traynor, Alan J. Warren, Emmanuel Giudice, Li Jin, Robert R. Kay, Christine Hilcenko, Mark J. Churcher, Chi C. Wong, Felix Weis, Department of Haematology, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Medical Research Council Laboratory of Molecular Biology, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), The Wellcome Trust Sanger Institute [Cambridge], Supported by a Federation of European Biochemical Societies Long termFellowship (to FW), Specialist Programme from Bloodwise [12048] (AJW), theMedical Research Council [MC_U105161083] (AJW) and [U105115237] (RRK),Wellcome Trust strategic award to the Cambridge Institute for Medal Research[100140], Tesni Parry Trust (AJW), Ted’s Gang (AJW) and the Cambridge NIHRBiomedical Research Centre., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, Hilcenko, Christine [0000-0002-9596-7833], Warren, Alan [0000-0001-9277-4553], and Apollo - University of Cambridge Repository

Subjects
Models, Molecular, Protein subunit, [SDV]Life Sciences [q-bio], Molecular Conformation, Protozoan Proteins, Diseases, Biology, Ribosome, Models, Biological, GTP Phosphohydrolases, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, Eukaryotic initiation factor, Humans, Dictyostelium, Eukaryotic Initiation Factors, Peptide Chain Initiation, Translational, Molecular Biology, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Cancer, 0303 health sciences, Eukaryotic Large Ribosomal Subunit, Cryoelectron Microscopy, Proteins, Ribosomal RNA, SBDS, Ribosome Subunits, Large, Eukaryotic, Peptide Elongation Factors, Molecular biology, Cell biology, [SDV] Life Sciences [q-bio], EIF6, Ribosome Subunits, 030220 oncology & carcinogenesis, RNA
Abstract

International audience; SBDS protein (deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits. However, the mechanism is completely unknown. Here, we present cryo-EM structures of human SBDS and SBDS-EFL1 bound to Dictyostelium discoideum 60S ribosomal subunits with and without endogenous eIF6. SBDS assesses the integrity of the peptidyl (P) site, bridging uL16 (mutated in T-cell acute lymphoblastic leukemia) with uL11 at the P-stalk base and the sarcin-ricin loop. Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. Our data reveal the conserved mechanism of eIF6 release, which is corrupted in both inherited and sporadic leukemias.

Published
2015
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5. Structural consequences of nucleophosmin mutations in acute myeloid leukemia

Author

Mark Bycroft, Christopher M. Johnson, Fiona M. Townsley, Charles G. Grummitt, Alan J. Warren, Warren, Alan [0000-0001-9277-4553], and Apollo - University of Cambridge Repository

Subjects
Models, Molecular, NPM1, Cytoplasm, Nucleolus, Mutant, Molecular Sequence Data, Molecular Conformation, Biology, medicine.disease_cause, Biochemistry, medicine, Animals, Humans, Amino Acid Sequence, Nuclear protein, Nuclear export signal, Molecular Biology, Cell Proliferation, Mutation, Nucleophosmin, Sequence Homology, Amino Acid, Tryptophan, Myeloid leukemia, Nuclear Proteins, Cell Biology, Molecular biology, Protein Structure, Tertiary, Leukemia, Myeloid, Acute, Protein Structure and Folding, Cell Nucleolus
Abstract

Mutations affecting NPM1 (nucleophosmin) are the most common genetic lesions found in acute myeloid leukemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumor suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukemic cells. This mutant phenotype is the result of the substitution of several C-terminal residues, including one or two conserved tryptophan residues, with a leucine-rich nuclear export signal. The exact molecular mechanism underlying the loss of nucleolar retention, and the role of the tryptophans, remains unknown. In this study we have determined the structure of an independently folded globular domain in the C terminus of NPM1 using NMR spectroscopy, and we report that the conserved tryptophans are critical for structure. This domain is necessary for the nucleolar targeting of NPM1 and is disrupted by mutations in AML with cytoplasmic NPM1. Furthermore, we identify conserved surface-exposed lysine residues that are functionally rather than structurally important for nucleolar localization. This study provides new focus for efforts to understand the pathogenesis of AML with cytoplasmic NPM1 and may be used to aid the design of small molecules that target the C-terminal domain of NPM1 to act as novel anti-proliferative and anti-leukemia therapeutics.

Published
2008

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