Staff Profile

Background

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BSc and PhD from London University. Based in Newcastle from 1993 to 1998 and from 2003 to present and in Edinburgh from 1998 to 2003.

Qualifications

BSc (London, 1982)
PhD (London, 1989)

Previous Positions

May 2003 - May 2006
Research Associate, NICR, Newcastle University.

Nov 1998 – Feb 2003
Senior Research Associate, Roslin Institute (Edinburgh).

Jan 1997 - Nov 1998
Senior Research Associate, Department of Biochemistry and Genetics, Newcastle University.

Jan 1993 - Jan 1997
Wellcome Postdoctoral Research Fellow, Department of Biochemistry and Genetics, Newcastle University.

Oct 1989 - Jan 1993
Postdoctoral Research Associate, Imperial Cancer Research Fund Molecular Oncology Unit, Hammersmith Hospital, London.

Jan 1986 Oct 1989
Research Assistant, Biochemistry Department, University College and Middlesex School of Medicine.

Jan 1983 Jan 1986
Research Technician, Immunology Department, St George's Hospital Medical School, University of London.

Informal Interests

Photography
Walking

Research Interests

My research interests fall into the areas DNA topoisomerases, vertebrate gene regulation, nuclear organization and function and DNA repair in particular relating to DNA topoisomerase II poisons. This is currently focussed on the following themes:

- DNA topoisomerase II beta (TOP2B) and its role in facilitating gene expression programs during differentiation and cell cycle exit.

-Can standard cancer therapies (especially TOP2 poison treatments) be modified to avoid serious short and long-term side effects?

-Targeting DNA-repair processes as a means on improving the efficacy of anti-cancer treatments

Previous research interests fall into the following areas
-Histone modifications, including methylation and acetylation and changes in chromatin/nuclear organisation associated with DNA damage.
-Histone lysine methylation and the function of chromo-domain proteins.

Other Expertise

My areas of research expertise include:
- Fluorescence microscopy including quantitative and qualitative immunofluorescence, DNA FISH and 3D RNA FISH.

-ChIP and DNA damage assays
- Cell toxicity and growth inhibition assays (eg Clonogenic and XTT assays).
- Culture and manipulation of murine and human embryonic stem cells and iPSC cells as well as other general cell biology techniques including siRNA knockdown.
- Antibody purification and other protein biochemical techniques.
- Molecular cloning techniques including the design and assembly of expression and other DNA constructs.
- General bioinformatics and IT expertise – this is currently increasing as we do more next-gen sequencing work.

Undergraduate Teaching

I contribute to 3rd year modules BMS3012 "Cancer Biology and Therapy", BGM3024 "The Molecular Basis of Cancer", and BGM3065 "Biochemistry of Cancer and Chronic Diseases" delivering lectures on carcinogenesis, apoptosis, DNA repair mechanisms and genome instability in cancer.

Postgraduate Teaching

PhD student supervision:

I am currently supervising one Postgraduate student.

Past postgraduate students:

2016-2019: Cellular and Regulatory Roles of human DNA topoisomerase II beta. Student Mushtaq Khazeem

2014-2018: Processing of TOP2-DNA complexes by the ubiquitin-proteasome system. Student, Rebecca Swan

2013-2017: Myeloperoxidase enhances DNA damage induced by drugs targeting DNA topoisomerase II. Student, Mandeep Atwal

2008-2012: The potential role of TOP2B in therapy related leukaemia. Student, Kayleigh Smith

2004-2007: Characterisation of DNA damage induced nuclear foci containing PML and TopBP1. Student, Nicola Sunter.

MSci/MRes

2018-2019: MRes project: Retinoid-induced cell-cycle exit and differentiation in neuroblastoma cells.

2016-2017: MRes project: Ligand Mediated Transcriptional Regulation by TOP2B. 

2014-2015: MSci Project: Investigating the individual roles of TOP2A and TOP2B in DNA damage induced by TOP2 poisons at the PML locus.

2012-2013: MSci project: Does CTCF contribute to chromosome translocations in leukaemia?

MPharm

2017-2018: Myeloperoxidase inhibitors: repurposing novel anti-inflammatory drugs to protect bone marrow after chemotherapy. 

MSc research project supervision:
The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure (1992) - (In my previous post at the Roslin Institute).

• Articles

  • Menger KE, Chapman J, Díaz-Maldonado H, Khazeem MM, Deen D, Erdinc D, Casement JW, Di Leo V, Pyle A, Rodríguez-Luis A, Cowell IG, Falkenberg M, Austin CA, Nicholls TJ. Two type I topoisomerases maintain DNA topology in human mitochondria. Nucleic Acids Research 2022, gkac857.
  • Khazeem mm, Casement JW, Scholssmacher G, Kenneth NS, Sumbung NK, Chan JYT, McGow JF, Cowell IG, Austin CA. TOP2B Is Required to Maintain the Adrenergic Neural Phenotype and for ATRA‑Induced Differentiation of SH‑SY5Y Neuroblastoma Cells. Molecular Neurobiology 2022, 59.
  • Broderick L, Blum RH, Clay GC, Liu Y, McVicar R, Papes F, Boosherhi LM, Cowell IG, Austin CA, Putnam CD, Kaufman DS. Disease-associated Mutations in Topoisomerase IIβ Result in Defective NK cells. Journal of Allergy and Clinical Immunology 2022, Epub ahead of print.
  • Ling EM, Baslé A, Cowell IG, van den Berg B, Blower TR, Austin CA. A comprehensive structural analysis of the ATPase domain of Human DNA topoisomerase II Beta bound to AMPPNP, ADP and the bisdioxopiperazine, ICRF193. Structure 2022, 30(8), 1129-1145.e3.
  • Swan RL, Cowell IG, Austin CA. A role for VCP/p97 in the processing of drug-stabilized TOP2-DNA covalent complexes. Molecular Pharmacology 2021, 100(1), 57-62.
  • Khazeem MM, Cowell IG, Harkin LF, Casement JW, Austin CA. Transcription of carbonyl reductase 1 is regulated by DNA topoisomerase II beta. FEBS Letters 2020, 594(20), 3395-3405.
  • Swan R, Poh L, Cowell IG, Austin CA. Small molecule inhibitors confirm ubiquitin-dependent removal of TOP2-DNA covalent complexes. Molecular pharmacology 2020, 98(2), 118893.
  • Cowell IG, Ling EM, Swan RL, Brooks MLW, Austin CA. The Deubiquitinating Enzyme Inhibitor PR-619 is a Potent DNA Topoisomerase II Poison s. Molecular Pharmacology 2019, 96(5), 562–572.
  • Broderick L, Yost S, Li D, McGeough MD, Booshehri LM, Guaderrama M, Brydges SD, Kucharova K, Patel NC, Harr M, Hakonarson H, Zackai E, Cowell IG, Austin CA, Hugle B, Gebauer C, Zhang J, Xu X, Wang J, Croker BA, Frazer KA, Putnam CD, Hoffman HM. Mutations in topoisomerase IIβ result in a B cell immunodeficiency. Nature Communications 2019, 10(1), 3644.
  • Atwal M, Swan RL, Rowe C, Lee KC, Lee DC, Armstrong L, Cowell IG, Austin CA. Intercalating TOP2 poisons attenuate topoisomerase action at higher concentrations. Molecular Pharmacology 2019, 96(4), 475-484.
  • Lee KC, Swan RL, Sondka Z, Padget K, Cowell IG, Austin CA. Effect of TDP2 on the level of TOP2-DNA complexes and SUMOylated TOP2-DNA complexes. International Journal of Molecular Sciences 2018, 19(7), 2056.
  • Atwal M, Lishman EL, Austin CA, Cowell IG. Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy. Molecular Pharmacology 2017, 91(1), 49-57.
  • Lee KC, Bramley RL, Cowell IG, Jackson GH, Austin CA. Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II. Biochemical Pharmacology 2016, 103, 29-39.
  • Manville CM, Smith K, Sondka Z, Rance H, Cockell S, Cowell IG, Lee KC, Morris NJ, Padget K, Jackson GH, Austin CA. Genome-wide ChIP-seq analysis of human TOP2B occupancy in MCF7 breast cancer epithelial cells. Biology Open 2015, 4(11), 1436-1447.
  • Ben-David U, Cowell IG, Austin CA, Benvenisty N. Brief Reports: Controlling the Survival of Human Pluripotent Stem Cells by Small Molecule-Based Targeting of Topoisomerase II Alpha. Stem Cells 2015, 33(3), 1013-1019.
  • Smith KA, Cowell IG, Zhang YM, Sondka Z, Austin CA. The role of topoisomerase II beta on breakage and proximity of RUNX1 to partner alleles RUNX1T1 and EVI1. Genes Chromosomes & Cancer 2014, 53(2), 117-128.
  • Best A, James K, Dalgliesh C, Hong EA, Kheirolahi-Kouhestani M, Curk T, Xu Y, Danilenko M, Hussain R, Keavney B, Wipat A, Klinck R, Cowell IG, Cheong Lee K, Austin C, Venables JP, Chabot B, Santibanez Koref M, Tyson-Capper AJ, Elliott DJ. Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons. Nature Communications 2014, 5, 4760.
  • Lee KC, Padget K, Curtis Hannah, Cowell IG, Moiani D, Sondka Z, Morris NK, Jackson GH, Cockell SJ, Tainer JA, Austin CA. MRE11 facilitates the removal of human topoisomerase II complexes from genomic DNA. Biology Open 2012, 1(9), 863-873.
  • Cowell IG, Sondka Z, Smith K, Lee KC, Manville CM, Sidorczuk-Lesthuruge M, Rance HA, Padget K, Jackson GH, Adachi N, Austin CA. Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity. Proceedings of the National Academy of Sciences 2012, 109(23), 8989-8994.
  • Cowell IG, Papageorgiou N, Padget K, Watters GP, Austin CA. Histone deacetylase inhibition redistributes topoisomerase IIβ from heterochromatin to euchromatin. Nucleus 2011, 2(1), 61-71.
  • Toyoda E, Kagaya S, Cowell IG, Kurosawa A, Kamoshita K, Nishikawa K, Iiizumi S, Koyama H, Austin CA, Adachi N. NK314, a Topoisomerase II inhibitor that specifically targets the α isoform. Journal of Biological Chemistry 2008, 283(35), 23711-23720.
  • Willmore E, Elliott SL, Mainou-Fowler T, Summerfield GP, Jackson GH, O'Neill F, Lowe C, Carter A, Harris R, Pettitt AR, Cano-Soumillac C, Griffin RJ, Cowell IG, Austin CA, Durkacz BW. DNA-dependent protein kinase is a therapeutic target and an indicator of poor prognosis in B-cell chronic lymphocytic leukemia. Clinical Cancer Research 2008, 14(12), 3984-3992.
  • Cowell I, Sunter NJ, Singh PB, Austin CA, Durkacz BW, Tilby MJ. γH2AX foci form preferentially in euchromatin after ionising-radiation. PLoS ONE 2007, 2(10), e1057.
  • Leontiou C, Watters GP, Gilroy KL, Heslop P, Cowell IG, Craig K, Lightowlers RN, Lakey JH, Austin CA. Differential selection of acridine resistance mutations in human DNA topoisomerase II beta is dependent on the acridine structure. Molecular Pharmacology 2007, 71(4), 1006-1014.
  • Zhao Y, Thomas HD, Batey M, Cowell I, Richardson C, Griffin RJ, Calvert AH, Newell DR, Smith G, Curtin NJ. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Research 2006, 66(10), 5354-5362.
  • Cowell, I.G., Durkacz, B.W., Tilby, M.J. Sensitization of breast carcinoma cells to ionizing radiation by small molecule inhibitors of DNA-dependent protein kinase and ataxia telangiectsia mutated. Biochemical Pharmacology 2005, 71(1-2), 13-20.
  • Brown JP, Singh PB, Cowell IG. Composite cis-acting epigenetic switches in eukaryotes: lessons from Drosophila Fab-7 for the Igf2-H19 imprinted domain. Genetica 2003, 117(2/3), 199-207.
  • Scholzen T, Endl E, Wohlenberg C, Sar SvanDer, Cowell IG, Gerdes J, Singh PB. The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure. Journal of Pathology 2002, 196(2), 135-144.
  • Filesi I, Cardinale A, van der Sar S, Cowell IG, Singh PB, Biocca S. Loss of Heterochromatin Protein 1 (HP1) chromodomain function in mammalian cells by intracellular antibodies causes cell death. Journal of Cell Science 2002, 115(9), 1803-1813.
  • Cowell IG, Aucott R, Mahadevaiah SK, Burgoyne PS, Huskisson NS, Bongiorni S, Prantera G, Fanti L, Pimpinelli S, Wu R, Gilbert D, Shi W, Fundele R, Morrison H, Jeppesen P, Singh PB. Heterochromatin, HP1 and methylation at lysine 9 of histone H3 in animals. Chromosoma 2002, 111(1), 22-36.
  • Cowell IG. E4BP4/NFIL3, a PAR-related bZIP factor with many roles. BioEssays 2002, 24(11), 1023-1029.
  • Jones DO, Mattei MG, Horsley D, Cowell IG, Singh PB. The gene and pseudogenes of Cbx3/mHP1 gamma. DNA sequence 2001, 12(3), 147-160.
  • Jones DO, Cowell IG, Singh PB. Mammalian chromodomain proteins: their role in genome organisation and expression. BioEssays 2000, 22(2), 124-137.
  • Kourmouli N, Theodoropoulos PA, Dialynas G, Bakou A, Politou AS, Cowell IG, Singh PB, Georgatos SD. Dynamic associations of heterochromatin protein 1 with the nuclear envelope. The EMBO Journal 2000, 19(23), 6558-6568.
  • Wang G, Ma A, Chow CM, Horsley D, Brown NR, Cowell IG, Singh PB. Conservation of heterochromatin protein 1 function. Molecular & Cellular Biology 2000, 20(18), 6970-6983.
  • Cowell IG, Willmore E, Chalton DA, Marsh KL, Jazrawi E, Fisher LM, Austin CA. Nuclear distribution of human DNA topoisomerase IIβ: A nuclear targeting signal resides in the 116-residue C-terminal tail. Experimental Cell Research 1998, 243(2), 232-240.
  • Cowell IG, Austin CA. Self-association of chromo domain peptides. Biochimica et Biophysica Acta: Protein Structure and Molecular Enzymology 1997, 1337(2), 198-206.
  • Cowell IG, Hurst HC. Protein-protein interaction between the transcriptional repressor E4BP4 and the TBP-binding protein Dr1. Nucleic Acids Research 1996, 24(18), 3607-3613.
  • Cowell IG, Hurst HC. Transcriptional repression by the human bZIP factor E4BP4: Definition of a minimal repression domain. Nucleic Acids Research 1994, 22(1), 59-65.
  • Spencer SR, Taylor JB, Cowell IG, Xia CL, Pemble SE, Ketterer B. The human mitochondrial NADH: Ubiquinone oxidoreductase 51-kDa subunit maps adjacent to the glutathione S-transferase p1-1 gene on chromosome 11q13. Genomics 1992, 14(4), 1116-1118.
  • Xia CL, Cowell IG, Dixon KH, Pemble SE, Ketterer B, Taylor JB. Glutathione transferase pi its minimal promoter and downstream cis- acting element. Biochemical and Biophysical Research Communications 1991, 176(1), 233-240.
  • Dixon KH, Cowell IG, Xia CL, Pemble SE, Ketterer B, Taylor JB. Control of expression of the human glutathione S-transferase Pi gene differs from its rat homologue. Biochemical and Biophysical Research Communications 1989, 163(2), 815-822.
  • Cowell IG, Dixon KH, Pemble SE, Ketterer B, Taylor JB. The structure of the human glutathione-Pi gene. Biochemical Journal 1988, 255(1), 79-83.
  • Taylor JB, Pemble SE, Cowell IG, Dixon KH, Ketterer B. Molecular biology of the glutathione transferases. Biochemical Society Transactions 1986, 15, 578-579.

• Book Chapters

  • Cowell IG, Austin CA. Visualization and quantification of topoisomerase–DNA covalent complexes using the trapped in agarose immunostaining (TARDIS) assay. In: DNA Topoisomerases: Methods and Protocols. New York: Humana Press, 2018, pp.301-316.
  • Smith KA, Cowell IG, Austin CA. Topoisomerase II chromatin immunoprecipitation. In: DNA Topoisomerases: Methods and Protocols. New York: Humana Press, 2018, pp.183-189.

• Reviews

  • Cowell IG, Austin CA. DNA fragility at the KMT2A/MLL locus: insights from old and new technologies. Open Biology 2023, 13(1), 220232.
  • Swan RL, Cowell IG, Austin CA. Mechanisms to Repair Stalled Topoisomerase II-DNA Covalent Complexes. Molecular Pharmacology 2022, 101(1), 24-32.
  • Austin CA, Cowell IG, Khazeem MM, Lok D, Ng HT. TOP2B’s contributions to transcription. Biochemical Society Transactions 2021.
  • Austin CA, Lee KC, Swan RL, Khazeem MM, Manville CM, Cridland P, Treumann A, Porter A, Morris NJ, Cowell IG. TOP2B: The first thirty years. International Journal of Molecular Sciences 2018, 19(9), 2765.
  • Cowell IG, Austin CA. Mechanism of Generation of Therapy Related Leukemia in Response to Anti-Topoisomerase II Agents. International Journal of Environmental Research and Public Health 2012, 9(6), 2075-2091.
  • Cowell IG, Austin CA. Do transcription factories and TOP2B provide a recipe for chromosome translocations in therapy-related leukemia?. Cell Cycle 2012, 11(17), 3143-3144.
  • Cowell IG, Tilby MJ, Austin CA. An overview of the visualisation and quantitation of low and high MW DNA adducts using the trapped in agarose DNA immunostaining (TARDIS) assay. Mutagenesis 2011, 26(2), 253-260.
  • Cowell IG. Repression versus activation in the control of gene transcription. Trends in Biochemical Sciences 1994, 19(1), 38-42.