Wellcome to the Bowman lab. We are based in the division of Biomedical Sciences at the University of Warwick, and are interested in how DNA is packaged within our cells. This is an important process as errors in the packaging mechanism can lead to genetic instability and DNA damage, processes linked to human pathologies such as cancer. News about goings-on in the lab can be found in the social media feeds below.
Research
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Our research focuses on the very first level of DNA packaging, the nucleosome. To form a nucleosome DNA is wrapped twice around a spool of proteins known as histones. We are interested in how components of these spools are manufactured and shipped to the correct location in the cell, how they package DNA into stable units, and thereby how they ensure genetic integrity for following generations. There is a lot of DNA in cells, all of which requires spooling into nucleosomes. It is unsurprising therefore that histones are one of the most abundant proteins. In fact they are so abundant that they have their own dedicated production line. Research in our lab is focussed on how this production line works and what happens when it goes wrong. |
The 3D structures of a number of H3-H4 chaperoning proteins bound to their histone cargo. Work in the Bowman lab is focussed on relating the thermodynamic process of nucleosome assembly with the ordered interactions between core histones and their chaperoning proteins.
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Recently we have developed a small-molecule, cytoplasmic tether-and-release system (RAPID-release) that enables us to probe rapid nuclear turnover events as they occur. Using this approach we have investigated the very early stages of a histone’s life: cytosolic binding events and nuclear import, something that has hitherto been challenging to observe. The movie to the left shows histones translocating from a cytosolic tether (the outer mitochondrial membrane) to the nucleus, triggered by the addition of a small molecule (rapamycin). The foci appearing at the end of the movie correlate to sites of replication where histones are being actively deposited onto DNA. This technique, therefore, represents a potential way to dissect the rapid binding events that occur between cytosolic release and chromatin incorporation. |
We are also investigating the relationship between nuclear architecture and chromosome folding in living cells. Outside of mitosis, chromosomes adopt a more relaxed structure in which chromatin fibres are organised into higher order domains known as TADs (Topological Associated Domains). These megabase domains have been shown to correlate with autonomous replication units (or Replication Domains - RDs).
A benefit of using fluorescently labelled histones to pulse label chromatin is that the RDs/TADs can be subsequently tracked in living cells, and unlike fluorescent nucleotides, are relatively inert and do not degrade rapidly. We are currently investigating the movement of these domains at a high spacial and temporal resolution, with light-sheet microscopy providing the potential to track domains over a number of cell generations with limited bleaching and phototoxicity.
The movie to below shows the nucleus of a cell in which late replicating chromatin has been labelled with H3.1-eGFP using the RAPID-release approach. An algorithm has then been used to track the TADs over time during the G2-phase of the cell cycle. Whilst the positions of most TADs are restricted to their initial location (around the nuclear lamina), a minority of TADs show dynamic movement over micron-scale distances (an example is traced with a blue line).
A benefit of using fluorescently labelled histones to pulse label chromatin is that the RDs/TADs can be subsequently tracked in living cells, and unlike fluorescent nucleotides, are relatively inert and do not degrade rapidly. We are currently investigating the movement of these domains at a high spacial and temporal resolution, with light-sheet microscopy providing the potential to track domains over a number of cell generations with limited bleaching and phototoxicity.
The movie to below shows the nucleus of a cell in which late replicating chromatin has been labelled with H3.1-eGFP using the RAPID-release approach. An algorithm has then been used to track the TADs over time during the G2-phase of the cell cycle. Whilst the positions of most TADs are restricted to their initial location (around the nuclear lamina), a minority of TADs show dynamic movement over micron-scale distances (an example is traced with a blue line).
People
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Andrew Bowman
Brief bio - 2023: Associate Professor, Warwick 2018 - 2023: Sir Henry Dale Fellow, Warwick 2015 - 2018: Independent Research Fellow, Warwick 2013-2015: Marie Curie Fellow, Munich 2011-2013: EMBO fellow, Munich 2010-2011: Research associate, Dundee 2006-2010: PhD student, Dundee 2002-2006: BSc Biochemistry, Leicester |
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Filipe Fernandes Duarte - Ph.D. Student
Fil, originally from Portugal, studied biochemistry & genetics at the University of Lancaster before joining the MRC-DTP graduate program. After a mini project in the lab during his MSc year, he decided to return to undertake his full PhD. Fil is combining tether-and-release approaches to observe the dynamics of replication domains in single, living cells by pulse-labelling chromatin with fluorescent histones. |
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Alonso Pardal - Postdoc
Alonso studied Pharmacy and Pharmacology and a Masters in Plant Biotechnology in the University of Salamanca (Spain). Following that, he moved to the University of Warwick to do his PhD with Vardis Ntoukakis working on the role of chromatin remodelling complexes in gene reprogramming during microbial infection Alonso is combining proximity labelling with the RAPID-release approach to study the kinetics of histone-chaperone interactions during their journey from ribosome to chromosome. |
Publications
View publications on Pubmed
Hasan Mamar, Roberta Fajka-Boja, Mónika Mórocz, Eva Pinto Jurado, Siham Zentout, Alexandra Mihuţ, Anna Georgina Kopasz, Mihály Mérey, Rebecca Smith, Abhishek Bharadwaj Sharma, Nicholas D Lakin, Andrew James Bowman, Lajos Haracska, Sébastien Huet, Gyula Timinszky (2024). The loss of DNA polymerase epsilon accessory subunits POLE3–POLE4 leads to BRCA1-independent PARP inhibitor sensitivity. Nucleic Acids Res. 52, 6994–7011.
Pardal A.J., Bowman A. J. (2022). A specific role of importin-5 and NASP in the import and nuclear hand-off of monomeric H3. eLife: https://elifesciences.org/articles/81755.
Pardal A.J., Fernandes-Duarte F., Bowman A.J. (2019). The histone chaperoning pathway: from ribosome to nucleosome. Essays Biochem. 63(1):29-43. Review.
Apta-Smith M.J., Hernandez-Fernaud J.R., Bowman A.J. (2018). Evidence for the nuclear import of histones H3.1 and H4 as monomers. EMBO J. doi:10.15252/embj.201798714.
Bowman, A., Koide, A., Goodman, J.S., Colling, M.E., Zinne, D., Koide, S., and Ladurner, A.G. (2017). sNASP and ASF1A function through both competitive and compatible modes of histone binding. Nucleic Acids Res 45, 643-656.
Bowman, A., Lercher, L., Singh, H.R., Zinne, D., Timinszky, G., Carlomagno, T., and Ladurner, A.G. (2016). The histone chaperone sNASP binds a conserved peptide motif within the globular core of histone H3 through its TPR repeats. Nucleic Acids Res 44, 3105-3117.
Bowman, A., Hammond, C.M., Stirling, A., Ward, R., Shang, W., El-Mkami, H., Robinson, D.A., Svergun, D.I., Norman, D.G., and Owen-Hughes, T. (2014). The histone chaperones Vps75 and Nap1 form ring-like, tetrameric structures in solution. Nucleic Acids Res 42, 6038-6051.
Zhang, W., Tyl, M., Ward, R., Sobott, F., Maman, J., Murthy, A.S., Watson, A.A., Fedorov, O., Bowman, A., Owen-Hughes, T., et al. (2013). Structural plasticity of histones H3-H4 facilitates their allosteric exchange between RbAp48 and ASF1. Nat Struct Mol Biol 20, 29-35.
Hondele, M., Stuwe, T., Hassler, M., Halbach, F., Bowman, A., Zhang, E.T., Nijmeijer, B., Kotthoff, C., Rybin, V., Amlacher, S., et al. (2013). Structural basis of histone H2A-H2B recognition by the essential chaperone FACT. Nature 499, 111-114.
Bowman, A., and Owen-Hughes, T. (2012). Sulfyhydryl-reactive site-directed cross-linking as a method for probing the tetrameric structure of histones H3 and H4. Methods Mol Biol 833, 373-387.
Bowman, A., Ward, R., Wiechens, N., Singh, V., El-Mkami, H., Norman, D.G., and Owen-Hughes, T. (2011). The histone chaperones Nap1 and Vps75 bind histones H3 and H4 in a tetrameric conformation. Mol Cell 41, 398-408.
Ward, R., Bowman, A., Sozudogru, E., El-Mkami, H., Owen-Hughes, T., and Norman, D.G. (2010). EPR distance measurements in deuterated proteins. J Magn Reson 207, 164-167.
Bowman, A., Ward, R., El-Mkami, H., Owen-Hughes, T., and Norman, D.G. (2010). Probing the (H3-H4)2 histone tetramer structure using pulsed EPR spectroscopy combined with site-directed spin labelling. Nucleic Acids Res 38, 695-707.
Ward, R., Bowman, A., El-Mkami, H., Owen-Hughes, T., and Norman, D.G. (2009). Long distance PELDOR measurements on the histone core particle. Journal of the American Chemical Society 131, 1348-1349.
Hasan Mamar, Roberta Fajka-Boja, Mónika Mórocz, Eva Pinto Jurado, Siham Zentout, Alexandra Mihuţ, Anna Georgina Kopasz, Mihály Mérey, Rebecca Smith, Abhishek Bharadwaj Sharma, Nicholas D Lakin, Andrew James Bowman, Lajos Haracska, Sébastien Huet, Gyula Timinszky (2024). The loss of DNA polymerase epsilon accessory subunits POLE3–POLE4 leads to BRCA1-independent PARP inhibitor sensitivity. Nucleic Acids Res. 52, 6994–7011.
Pardal A.J., Bowman A. J. (2022). A specific role of importin-5 and NASP in the import and nuclear hand-off of monomeric H3. eLife: https://elifesciences.org/articles/81755.
Pardal A.J., Fernandes-Duarte F., Bowman A.J. (2019). The histone chaperoning pathway: from ribosome to nucleosome. Essays Biochem. 63(1):29-43. Review.
Apta-Smith M.J., Hernandez-Fernaud J.R., Bowman A.J. (2018). Evidence for the nuclear import of histones H3.1 and H4 as monomers. EMBO J. doi:10.15252/embj.201798714.
Bowman, A., Koide, A., Goodman, J.S., Colling, M.E., Zinne, D., Koide, S., and Ladurner, A.G. (2017). sNASP and ASF1A function through both competitive and compatible modes of histone binding. Nucleic Acids Res 45, 643-656.
Bowman, A., Lercher, L., Singh, H.R., Zinne, D., Timinszky, G., Carlomagno, T., and Ladurner, A.G. (2016). The histone chaperone sNASP binds a conserved peptide motif within the globular core of histone H3 through its TPR repeats. Nucleic Acids Res 44, 3105-3117.
Bowman, A., Hammond, C.M., Stirling, A., Ward, R., Shang, W., El-Mkami, H., Robinson, D.A., Svergun, D.I., Norman, D.G., and Owen-Hughes, T. (2014). The histone chaperones Vps75 and Nap1 form ring-like, tetrameric structures in solution. Nucleic Acids Res 42, 6038-6051.
Zhang, W., Tyl, M., Ward, R., Sobott, F., Maman, J., Murthy, A.S., Watson, A.A., Fedorov, O., Bowman, A., Owen-Hughes, T., et al. (2013). Structural plasticity of histones H3-H4 facilitates their allosteric exchange between RbAp48 and ASF1. Nat Struct Mol Biol 20, 29-35.
Hondele, M., Stuwe, T., Hassler, M., Halbach, F., Bowman, A., Zhang, E.T., Nijmeijer, B., Kotthoff, C., Rybin, V., Amlacher, S., et al. (2013). Structural basis of histone H2A-H2B recognition by the essential chaperone FACT. Nature 499, 111-114.
Bowman, A., and Owen-Hughes, T. (2012). Sulfyhydryl-reactive site-directed cross-linking as a method for probing the tetrameric structure of histones H3 and H4. Methods Mol Biol 833, 373-387.
Bowman, A., Ward, R., Wiechens, N., Singh, V., El-Mkami, H., Norman, D.G., and Owen-Hughes, T. (2011). The histone chaperones Nap1 and Vps75 bind histones H3 and H4 in a tetrameric conformation. Mol Cell 41, 398-408.
Ward, R., Bowman, A., Sozudogru, E., El-Mkami, H., Owen-Hughes, T., and Norman, D.G. (2010). EPR distance measurements in deuterated proteins. J Magn Reson 207, 164-167.
Bowman, A., Ward, R., El-Mkami, H., Owen-Hughes, T., and Norman, D.G. (2010). Probing the (H3-H4)2 histone tetramer structure using pulsed EPR spectroscopy combined with site-directed spin labelling. Nucleic Acids Res 38, 695-707.
Ward, R., Bowman, A., El-Mkami, H., Owen-Hughes, T., and Norman, D.G. (2009). Long distance PELDOR measurements on the histone core particle. Journal of the American Chemical Society 131, 1348-1349.
Engaging the Public
The Bowman lab looks to actively engage with a wider audience and has organised a number of public engagement events. We are always on the lookout for novel ways to spark the public's interest in fundamental research!
British Science Festival - University of Warwick, Sept 2019
Fil joined the Warwick QBP team to deliver a practical in DNA extraction at the British Science Festival!
Cafe Scientifique - Leamington Spa, April 2019
Fil Duarte presented his Ph.D. project in a Cafe Scientifique talk in Leamington Spa!
U3A talk - Warwick, 25th Apr 2018
Andrew gave a talk to the Warwick division of the University of the Third Age on 'Gene Editing', with practical demonstrations on how to decode DNA, therapeutic strategies to cure sickle cell anaemia, and precision genome engineering using CRISPR-Cas9!
Cell Biology Image Competition, 23rd Mar 2018
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Bowman lab submits two entries to the Warwick QBP 'Cell-fie' competition. One depicting a mysterious entity appearing out of nowhere, and the other depicting Batman. Winning images will go on display at the UHCW and other public spaces around Coventry and Warwickshire!
Pecha Kucha evening - Coventry, 29th June 2017
With support from the Warwick Quantitative Biology Program we organised a Pecha Kucha evening at The Tin in Coventry. Speakers from Warwick Medical School gave 20x20 presentations (20 slides, 20 seconds each) on their research, with guest speakers from the University of Birmingham (Ferenc Mueller), Tel Aviv University (Oded Rechavi) and The University of Oxford (Jane Mellor).
Our Supporters
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Contact
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Our lab is situated in the Mechanochemical Cell Biology Building (MCBB), and are part of the Biomedical Sciences Division within Warwick Medical School.
Email: a.bowman.1 at warwick.ac.uk MCBB, room L1.37 Warwick Medical School University of Warwick Gibbet Hill Road Coventry CV4 7AL United Kingdom |
