Professor Carl Smythe
School of Biosciences
Chair in Cell Biology
Director of the Mass Spectrometry Centre
+44 114 222 4643
Full contact details
School of Biosciences
E03a Florey Building
Firth Court
Western Bank
Sheffield
S10 2TN
- Profile
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- 2002 – present: Professor of Cell Biology, School of Biosciences, University of Sheffield
- 2004 – 2006: Head of Department, Department of Biomedical Science, University of Sheffield
- 1992 – 2002: Principal Investigator at MRC Protein Phosphorylation Unit, University of Dundee
- 1989 – 1992: American Cancer Society Senior Research Fellow, University of California, San Diego
- 1985 – 1989: British Diabetic Association postdoctoral research assistant at MRC Protein Phosphorylation Group at University of Dundee
- 1981 – 1985: PhD Department of Biochemistry, Trinity College, University of Dublin
- Research interests
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Chromosome integrity
Chromosomes in eukaryotes control their environment to ensure that genomic integrity is maximised. We are interested in understanding mechanisms of genomic integrity operating at the molecular and cellular level, and determining the consequences when they fail.
Cellular surveillance systems and their role in healthy aging
Research in our laboratory uses molecular cell biology approaches to understand quality control or surveillance mechanisms that operate in cells to ensure fidelity of function, the consequences when they fail, and how they may be exploited to ameliorate disease.
Examples include the replication checkpoint, which operates to ensure that cells experiencing replication stress, can evoke appropriate DNA damage responses, reschedule cell cycle events, or initiate apoptosis, and quality control systems regulating processes involving RNA homeostasis, such as nonsense-mediated decay (NMD), histone mRNA decay (HD), and telomere stability.
We utilise a variety of disease cell models in mechanistic studies and utilise whole genome and new chemical entity (NCE) screening together with mass spectrometry and imaging techniques, coupled with in vitro assays, to synergistically probe both biological and NCE function.
Our chemical biology work focuses on exploring the use of ruthenium co-ordination complexes to explore novel chemical space affecting pathways of interest, as well as novel indole polycyclic derivatives that block NMD.
Our focus is to identify potential new therapeutic targets in relevant disease models, and our work on the replication checkpoint has identified a number of proteins and /or pathways which are of interest.
Future directions
A key focus concerns the functional characterisation of the DNA /RNA helicase Upf1 which acts pleiotropically to regulate NMD, HD and telomere integrity. We have identified a novel NMD inhibitor which, importantly, does not affect histone mRNA regulation or telomere integrity.
We aim to utilise our expertise in genomic integrity and mass spectrometry to identify the target of this inhibitor as a potential therapeutic strategy for the treatment of nonsense mutation-associated disease.
- Publications
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Show: Featured publications All publications
Featured publications
Journal articles
- Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay. Org. Biomol. Chem., 14(5), 1559-1563. View this article in WRRO
- Designing a broad-spectrum integrative approach for cancer prevention and treatment. Seminars in Cancer Biology, 35, S276-S304. View this article in WRRO
- A Cytostatic Ruthenium(II)–Platinum(II) Bis(terpyridyl) Anticancer Complex That Blocks Entry into S Phase by Up-regulating p27KIP1. Chemistry - A European Journal, 21(25), 9185-9197. View this article in WRRO
- Dinuclear ruthenium(II) complexes as two-photon, time-resolved emission microscopy probes for cellular DNA.. Angew Chem Int Ed Engl, 53(13), 3367-3371. View this article in WRRO
- A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells. NAT CHEM, 1(8), 662-667.
- DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication. Journal of Cell Biology, 179(7), 1385-1398. View this article in WRRO
- ATM is required for the cellular response to thymidine induced replication fork stress.. Hum Mol Genet, 13(23), 2937-2945.
- Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. JOURNAL OF CELL BIOLOGY, 154(5), 913-923. View this article in WRRO
- klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes. PLoS ONE, 10(10). View this article in WRRO
All publications
Journal articles
- 5′-Methylthioadenosine strongly suppresses RANKL-induced osteoclast differentiation and function via inhibition of RANK-NFATc1 signalling pathways. Heliyon, 9(11), e22365-e22365.
- Targets, mechanisms and cytotoxicity of half-sandwich Ir(III) complexes are modulated by structural modifications on the benzazole ancillary ligand. Cancers, 15(1).
- Anticancer mechanism of 7-α-hydroxyfrullanolide on microtubules and computational prediction of its target binding in triple-negative breast cancer cells.. PeerJ, 10, e13508.
- A Ruthenium(II) Polypyridyl Complex Disrupts Actin Cytoskeleton Assembly and Blocks Cytokinesis.. Angew Chem Weinheim Bergstr Ger, 134(27), e202117449.
- A ruthenium(II) polypyridyl complex disrupts actin cytoskeleton assembly and blocks cytokinesis. Angewandte Chemie International Edition, 61(27).
- Enhancing activity of Pleurotus sajor-caju (Fr.) Sing β-1,3-Glucanoligosaccharide (Ps-GOS) on proliferation, differentiation, and mineralization of MC3T3-E1 cells through the involvement of BMP-2/Runx2/MAPK/Wnt/β-catenin signaling pathway. Biomolecules, 10(2). View this article in WRRO
- Making the right link to theranostics : the photophysical and biological properties of dinuclear Ru^II-Re^I dppz complexes depend on their tether. Journal of the American Chemical Society. View this article in WRRO
- Using Nanoscopy To Probe the Biological Activity of Antimicrobial Leads That Display Potent Activity against Pathogenic, Multidrug Resistant, Gram-Negative Bacteria. ACS Nano, 13(5), 5133-5146. View this article in WRRO
- Exploring the cytotoxicity, uptake, cellular response, and proteomics of mono- and dinuclear DNA light-switch complexes. Journal of the American Chemical Society, 141(7), 2925-2937. View this article in WRRO
- Two photon excitable graphene quantum dots for structured illumination microscopy and imaging applications: lysosome specificity and tissue-dependent imaging. Chemical Communications. View this article in WRRO
- l-Quebrachitol Promotes the Proliferation, Differentiation, and Mineralization of MC3T3-E1 Cells: Involvement of the BMP-2/Runx2/MAPK/Wnt/β-Catenin Signaling Pathway. Molecules, 23(12). View this article in WRRO
- A Fluorescent Chemodosimeter for Organelle-Specific Imaging of Nucleoside Polyphosphate Dynamics in Living Cells. Crystal Growth and Design, 18(11), 7199-7206. View this article in WRRO
- Mitochondria Targeting Non-isocyanate-based Polyurethane Nanocapsules for Enzyme-Triggered Drug Release. Bioconjugate Chemistry. View this article in WRRO
- Polysulfide-triggered fluorescent indicator suitable for super-resolution microscopy and application in imaging. Chemical Communications, 54(30), 3735-3738. View this article in WRRO
- Mitochondria-localising DNA-binding biscyclometalated phenyltriazole iridium(iii) dipyridophenazene complexes: Syntheses and cellular imaging properties. Dalton Transactions, 47(14), 4931-4940. View this article in WRRO
- Tracking HOCl concentrations across cellular organelles in real time using a super resolution microscopy probe. Chemical Communications, 54(15), 1849-1852. View this article in WRRO
- A Super Resolution Probe to Monitor HNO Levels in the Endoplasmic Reticulum of Cells.. Analytical Chemistry, 89(22), 12087-12093. View this article in WRRO
- A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(II) metallo-intercalator. Chemical Science, 9, 841-849. View this article in WRRO
- Multimodal Super-resolution Optical Microscopy Using a Transition-Metal-Based Probe Provides Unprecedented Capabilities for Imaging Both Nuclear Chromatin and Mitochondria. Journal of the American Chemical Society, 139(44), 15907-15913. View this article in WRRO
- Imaging cellular trafficking processes in real time using lysosome targeted up-conversion nanoparticles.. Chemical Communications, 53, 12672-12675. View this article in WRRO
- Homo- and heteroleptic phototoxic dinuclear metallo-intercalators based on RuII(dppn) intercalating moieties: synthesis, optical and biological studies. Angewandte Chemie International Edition, 129(41), 12802-128007. View this article in WRRO
- A Self‐Assembled Metallomacrocycle Singlet Oxygen Sensitizer for Photodynamic Therapy. Chemistry - A European Journal, 22(17), 5996-6000. View this article in WRRO
- Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay. Org. Biomol. Chem., 14(5), 1559-1563. View this article in WRRO
- Designing a broad-spectrum integrative approach for cancer prevention and treatment. Seminars in Cancer Biology, 35, S276-S304. View this article in WRRO
- Serum Albumin Binding Inhibits Nuclear Uptake of Luminescent Metal-Complex-Based DNA Imaging Probes. Chemistry - A European Journal, 21(33), 11865-11871.
- A Cytostatic Ruthenium(II)–Platinum(II) Bis(terpyridyl) Anticancer Complex That Blocks Entry into S Phase by Up-regulating p27KIP1. Chemistry - A European Journal, 21(25), 9185-9197. View this article in WRRO
- Tuning the Cellular Uptake Properties of Luminescent Heterobimetallic Iridium(III)-Ruthenium(II) DNA Imaging Probes. Chemistry - A European Journal, 20(43), 14004-14011.
- Dinuclear ruthenium(II) complexes as two-photon, time-resolved emission microscopy probes for cellular DNA.. Angew Chem Int Ed Engl, 53(13), 3367-3371. View this article in WRRO
- Targeting the endoplasmic reticulum with a membrane-interactive luminescent ruthenium(II) polypyridyl complex. Chemical Science. View this article in WRRO
- Ruthenium(II) metallo-intercalators: DNA imaging and cytotoxicity.. Chembiochem, 12(6), 877-880.
- Hyphal growth in Candida albicans requires the phosphorylation of Sec2 by the Cdc28-Ccn1/Hgc1 kinase.. EMBO J, 29(17), 2930-2942.
- A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells. NAT CHEM, 1(8), 662-667.
- DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication. Journal of Cell Biology, 180(4), 843-843.
- NEP-A and NEP-B both contribute to nuclear pore formation in Xenopus eggs and oocytes. Journal of Cell Science, 121(5), 706-716.
- DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication. Journal of Cell Biology, 179(7), 1385-1398. View this article in WRRO
- ATM is required for the cellular response to thymidine induced replication fork stress.. Hum Mol Genet, 13(23), 2937-2945.
- Clathrin promotes incorporation of cargo into coated pits by activation of the AP2 adaptor micro2 kinase.. J Cell Biol, 163(2), 231-236. View this article in WRRO
- Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366. Biochemical Journal, 368(2), 507-516.
- Purification and identification of secernin, a novel cytosolic protein that regulates exocytosis in mast cells. MOLECULAR BIOLOGY OF THE CELL, 13(9), 3344-3354.
- Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. JOURNAL OF CELL BIOLOGY, 154(5), 913-923. View this article in WRRO
- INCENP binds the Aurora-related kinase AIRK2 and is required to target it to chromosomes, the central spindle and cleavage furrow. Current Biology, 10(17), 1075-1078.
- Assembly of U7 small nuclear ribonucleoprotein particle and histone RNA 3 ' processing in Xenopus egg extracts. JOURNAL OF BIOLOGICAL CHEMISTRY, 275(32), 24284-24293.
- ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. ONCOGENE, 18(48), 6707-6713.
- Biochemical characterisation of ATR protein kinase. Biochemical Society Transactions, 27(3), A97-A97.
- Temporal differences in the appearance of NEP-B78 and an LBR-like protein during Xenopus nuclear envelope reassembly reflect the ordered recruitment of functionally discrete vesicle types. JOURNAL OF CELL BIOLOGY, 144(2), 225-240. View this article in WRRO
- PD98059 prevents establishment of the spindle assembly checkpoint and inhibits the G(2)-M transition in meiotic but not mitotic cell cycles in Xenopus. EXPERIMENTAL CELL RESEARCH, 241(1), 12-22.
- NEP-B78 is a novel integral nuclear membrane protein involved in nuclear envelope precursor vesicle targeting to chromatin.. MOLECULAR BIOLOGY OF THE CELL, 8, 608-608.
- Cell-cycle arrest and inhibition of Cdk4 activity by small peptides based on the carboxy-terminal domain of p21(WAF1). CURRENT BIOLOGY, 7(1), 71-80.
- Activation of the Xenopus cyclin degradation machinery by full-length cyclin A. JOURNAL OF CELL SCIENCE, 109, 1071-1079.
- Isolation and characterisation of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54(jnk). ONCOGENE, 11(12), 2553-2563.
- XCL100, AN INDUCIBLE NUCLEAR MAP KINASE PHOSPHATASE FROM XENOPUS-LAEVIS - ITS ROLE IN MAP KINASE INACTIVATION IN DIFFERENTIATED CELLS AND ITS EXPRESSION DURING EARLY DEVELOPMENT. JOURNAL OF CELL SCIENCE, 108, 2885-2896.
- THE ROLE OF B-TYPE LAMINS IN THE ASSEMBLY OF A REPLICATION COMPETENT NUCLEUS. JOURNAL OF CELLULAR BIOCHEMISTRY, 123-123.
- IDENTIFICATION OF NOVEL REGULATORY EVENTS IN NUCLEAR-ENVELOPE REASSEMBLY USING XENOPUS EGG EXTRACTS. JOURNAL OF CELLULAR BIOCHEMISTRY, 94-94.
- MONOCLONAL-ANTIBODIES TO STRUCTURAL ELEMENTS OF AMPHIBIAN NUCLEAR ENVELOPES. JOURNAL OF CELLULAR BIOCHEMISTRY, 90-90.
- THE HUMAN CL100 GENE ENCODES A TYR/THR-PROTEIN PHOSPHATASE WHICH POTENTLY AND SPECIFICALLY INACTIVATES MAP KINASE AND SUPPRESSES ITS ACTIVATION BY ONCOGENIC RAS IN XENOPUS-OOCYTE EXTRACTS. ONCOGENE, 8(7), 2015-2020.
- In vitro cell cycle arrest induced by using artificial DNA templates.. Molecular and Cellular Biology, 12(7), 3216-3223.
- COUPLING OF MITOSIS TO THE COMPLETION OF S PHASE IN XENOPUS OCCURS VIA MODULATION OF THE TYROSINE KINASE THAT PHOSPHORYLATES P34CDC2. CELL, 68(4), 787-797.
- Chapter 17 Systems for the Study of Nuclear Assembly, DNA Replication, and Nuclear Breakdown in Xenopus laevis Egg Extracts, 449-468.
- THE DISCOVERY OF GLYCOGENIN AND THE PRIMING MECHANISM FOR GLYCOGEN BIOGENESIS. EUROPEAN JOURNAL OF BIOCHEMISTRY, 200(3), 625-631.
- ASSEMBLY DISASSEMBLY OF THE NUCLEAR-ENVELOPE MEMBRANE - CELL-CYCLE DEPENDENT BINDING OF NUCLEAR-MEMBRANE VESICLES TO CHROMATIN INVITRO. CELL, 65(2), 209-217.
- TARGETING OF PROTEIN PHOSPHATASE-1 TO THE SARCOPLASMIC-RETICULUM OF RABBIT SKELETAL-MUSCLE BY A PROTEIN THAT IS VERY SIMILAR OR IDENTICAL TO THE G-SUBUNIT THAT DIRECTS THE ENZYME TO GLYCOGEN. EUROPEAN JOURNAL OF BIOCHEMISTRY, 189(2), 243-249.
- FURTHER-STUDIES ON THE ROLE OF GLYCOGENIN IN GLYCOGEN BIOSYNTHESIS. EUROPEAN JOURNAL OF BIOCHEMISTRY, 189(1), 199-204.
- STRUCTURAL AND FUNCTIONAL-STUDIES ON RABBIT LIVER GLYCOGENIN. EUROPEAN JOURNAL OF BIOCHEMISTRY, 183(1), 205-209.
- GLYCOGENIN IS THE PRIMING GLUCOSYLTRANSFERASE REQUIRED FOR THE INITIATION OF GLYCOGEN BIOGENESIS IN RABBIT SKELETAL-MUSCLE. EUROPEAN JOURNAL OF BIOCHEMISTRY, 176(2), 391-395.
- ISOLATION AND STRUCTURAL-ANALYSIS OF A PEPTIDE CONTAINING THE NOVEL TYROSYL GLUCOSE LINKAGE IN GLYCOGENIN. EMBO JOURNAL, 7(9), 2681-2686.
- IDENTIFICATION OF THE 38-KDA SUBUNIT OF RABBIT SKELETAL-MUSCLE GLYCOGEN-SYNTHASE AS GLYCOGENIN. EUROPEAN JOURNAL OF BIOCHEMISTRY, 169(3), 497-502.
- SENP3-FIS1 axis promotes mitophagy and cell survival under hypoxia. Cell Death & Disease, 15(12).
- Pleurotus sajor-caju (Fr.) Singer β-1,3-Glucanoligosaccharide (Ps-GOS) Suppresses RANKL-Induced Osteoclast Differentiation and Function in Pre-Osteoclastic RAW 264.7 Cells by Inhibiting the RANK/NFκB/cFOS/NFATc1 Signalling Pathway. Molecules, 29(9), 2113-2113.
- Phenazine Cations as Anticancer Theranostics. Journal of the American Chemical Society.
- From Chemotherapy to Phototherapy – Changing the Therapeutic Action of a Metallo‐Intercalating Ru II ‐Re I Luminescent System by Switching its Sub‐Cellular Location. Chemistry – A European Journal.
- A Dinuclear Osmium(II) Complex Near-Infrared Nanoscopy Probe for Nuclear DNA. Journal of the American Chemical Society.
- Dinuclear osmium(ii) probes for high-resolution visualisation of cellular DNA structure using electron microscopy. Chem. Commun., 50(93), 14494-14497.
- DNA Replication and Progression Through the Cell Cycle, 161-186.
- klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes. PLoS ONE, 10(10). View this article in WRRO
Chapters
- The discovery of glycogenin and the priming mechanism for glycogen biogenesis, EJB Reviews 1991 (pp. 149-155). Springer Berlin Heidelberg
Conference proceedings papers
- Analysis of the Mechanism of DNA Damage and Replication Arrest-induced Histone mRNA DecayPornpen Panomwan*and Carl Smythe. FASEB JOURNAL, Vol. 29
- Analysis of the mechanism of DNA damage and replication arrest-induced histone mRNA decay. FEBS JOURNAL, Vol. 281 (pp 65-65)
- Ruthenium(II) polypyridyl complexes: In cellulo DNA binding and cytotoxicity. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, Vol. 241
- Are multiple checkpoint mediators involved in a checkpoint linking histone gene expression with DNA replication?. BIOCHEMICAL SOCIETY TRANSACTIONS, Vol. 35 (pp 1369-1371)
- Role of BRCT motif containing proteins in Chk1 activation. BREAST CANCER RESEARCH, Vol. 8 (pp S5-S6)
- The role of mitotic vesicles in the nuclear assembly. CELLULAR & MOLECULAR BIOLOGY LETTERS, Vol. 7(2) (pp 299-299)
- Incorporation of the nuclear pore basket protein Nup 153 into nuclear pore structures is dependent upon lamina assembly: evidence from cell-free extracts of Xenopus eggs. EMBO JOURNAL, Vol. 19(15) (pp 3918-3931)
- Research group
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Key collaborators
- Prof Iain Coldham, Dept of Chemistry, University of Sheffield
- Dr James Thomas, Dept of Chemistry, University of Sheffield
- Dr Sarah Danson, Dept of Oncology, University of Sheffield
- Dr Ferdinando Di Cunto, Department of Genetics, Biology& Biochemistry, University of Torino.
- Grants
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- Cystic Fibrosis Trust
- Yorkshire Cancer Research
- Royal Thai Higher Education Commission
- Malaysia Trust Council (Majlis Amanah Rakyat)
- Teaching activities
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Undergraduate and postgraduate taught modules
Undergraduate:
- BMS109-106 Pathobiology
- BMS379 Cancer Biology (Co-ordinator)
Masters (MSc):
- BMS6057 Cancer Biology (Co-ordinator)