Oxygenases and Cancer
Modification of proteins alters their function and allows cells to control critical processes such as cell growth and death. Inappropriate control of these modifications is a hallmark of several major diseases, including cancer. Our group studies proteins modified by oxygen, a process termed ‘hydroxylation’, and aims to understand how deregulated hydroxylation contributes to cancer.
Our Research Group
Our group aims to explore the role of a novel family of enzymes known as ‘2-oxoglutarate oxygenases’ in cancer. These enzymes depend on 2-oxoglutarate (2OG), oxygen and Fe(II) to catalyse oxidative modifications such as hydroxylation and demethylation. 2OG-oxygenases have been linked to cancer following their known involvement in hypoxia signalling and epigenetic regulation, and their altered expression, amplification and mutation observed in cancer genetics programs.
We have shown that a sub-set of 2OG-oxygenases hydroxylate substrates involved in the control of protein synthesis, including ribosomal proteins Rpl27a and Rpl8. Interestingly, the expression of these enzymes is deregulated in multiple tumour types. Since aberrant protein synthesis and translational control are critical features of cancer development and progression, our group aims to understand how regulation of protein translation by hydroxylation may contribute to tumourigenesis.
Our research on 2OG-oxygenases in cancer involves a multi-disciplinary approach that includes in vitro biochemical assays (interaction and enzyme modification assays, crystallography), gene knockout and RNA interference in tumour cell lines, and model organisms. In order to achieve this breadth of research we collaborate with several UK and international groups including Professor’s Peter Ratcliffe, Christopher Schofield, Xin Lu, Benedikt Kessler and Adrian Harris (Oxford), Professor Anne Willis (Leicester), Associate Professor Mark Bix (Memphis), Dr Stephen Renshaw (Sheffield), Dr Marion Schmidt-Zachmann (Heidelberg) and Dr Elena Alkalaeva and Professor Ludmila Frolova (Moscow).
- Systemic silencing of PHD2 causes reversible immune regulatory dysfunction. Yamamoto A, Hester J, Macklin PS, Kawai K, Uchiyama M, Biggs D, Bishop T, Bull K, Cheng X, Cawthorne E, Coleman ML, Crockford TL, Davies B, Dow LE, Goldin R, Kranc K, Kudo H, Lawson H, McAuliffe J, Milward K, Scudamore CL, Soilleux E, Issa F, Ratcliffe PJ, Pugh CW. J Clin Invest. 2019 Jun 4;13.
- Myc-induced nuclear antigen constrains a latent intestinal epithelial cell-intrinsic anthelmintic pathway. Pillai MR, Mihi B, Ishiwata K, Nakamura K, Sakuragi N, Finkelstein DB, McGargill MA, Nakayama T, Ayabe T, Coleman ML, Bix M. PLoS One. 2019 Feb 26;14(2).
- Bundred JR, Hendrix E, Coleman ML. 2018. The emerging roles of ribosomal histidyl hydroxylases in cell biology, physiology and disease. Cell Mol Life Sci. 75(22):4093-4105.
- Markolovic S, Zhuang Q, Wilkins SE, Eaton CD, Abboud MI, Katz MJ, McNeil HE, Leśniak RK, Hall C, Struwe WB, Konietzny R, Davis S, Yang M, Ge W, Benesch JLP, Kessler BM, Ratcliffe PJ, Cockman ME, Fischer R, Wappner P, Chowdhury R, Coleman ML*, Schofield CJ*. 2018. The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases. Nature Chemical Biology. *Equal contribution and corresponding author.
- Ploumakis A and Coleman ML, 2015. OH, the Places You’ll Go! Hydroxylation, Gene expression and Cancer. Molecular Cell. 58 (5), 729-41
- Zhuang QQ, Feng T, and Coleman ML, 2015. Modifying the maker: Oxygenases target ribosome biology. Translation. 3 (1), e1009331Singleton RS, Liu-Yi P, Formenti F, Ge W, Sekirnik R, Fischer R, Adam J, Pollard PJ, Wolf A, Thalhammer A, Loenarz C, Flashman E, Yamamoto A, Coleman ML, Kessler BM, Wappner P, Schofield CJ, Ratcliffe PJ, Cockman ME. 2014, OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation. PNAS, 111(11):4031-6.
- Tianshu Feng, Atsushi Yamamoto, Sarah E. Wilkins, Elizaveta Sokolova, Luke A. Yates,Martin Münzel, Pooja Singh, Richard J. Hopkinson, Roman Fischer, Matthew E. Cockman, Jake Shelley, David C. Trudgian, Johannes Schödel, James S. O. McCullagh, Wei Ge, Benedikt M. Kessler, Robert J. Gilbert, Ludmila Y. Frolova, Elena Alkalaeva, Peter J. Ratcliffe, Christopher J. Schofield, and Mathew L. Coleman, 2014, Optimal Translational Termination Requires C-4 Lysyl Hydroxylation of eRF1, Molecular Cell, 53(4), 645-54. Front Cover
- Yosef N, Shalek AK, Gaublomme JT, Jin H , Lee Y, Awasthi A, Wu C, Karwacz K, Xiao S, Jorgolli M, Gennert D, Satija R, Shakya A, Lu DY, Trombetta JJ, Pillai MR, Ratcliffe PJ, Coleman ML, Bix M, Tantin D, Park H, Kuchroo VK, Regev A, 2013, Dynamic regulatory network controlling Th17 cell differentiation, Nature, 496, 461-468.
- Ge W, Wolf A, Feng T, Ho CH, Sekirnik R, Zayer A, Granatino N, Cockman ME, Loenarz C, Loik ND, Hardy AP, Claridge TD, Hamed RB, Chowdhury R, Gong L, Robinson CV, Trudgian DC, Jiang M, Mackeen MM, McCullagh JS, Gordiyenko Y, Thalhammer A, Yamamoto A, Yang M, Liu-Yi P, Zhang Z, Schmidt-Zachmann M, Kessler BM, Ratcliffe PJ, Preston GM, Coleman ML*, Schofield CJ*, 2012, Oxygenase catalysed ribosome hydroxylation is conserved from prokaryotes to humans, Nature Chemical Biology, 8, 960-962. *Equal contribution and corresponding author.
- Yang M, Ge W, Chowdhury R, Claridge TD, Kramer HB, McDonough MA, Kessler BM, Ratcliffe PJ, Coleman ML*,Schofield CJ*, 2011, Asparaginyl and aspartyl hydroxylation of the cytoskeletal ankyrin family is catalysed by factor inhibiting hypoxia-inducible factor (FIH), J Biol Chem,286, 7648-60. *contributed equally.
- Webb JD, Murányi A, Pugh CW, Ratcliffe PJ, and Coleman ML, 2009, MYPT1, the targeting subunit of smooth-muscle myosin phosphatase, is a substrate for the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH), Biochem J,420, 327-33.
Dr Mathew Coleman
Dr Sally Fletcher
Dr Regina Andrijes
Dr Qinqin Zhuang
We always welcome enquiries from other talented researchers interested in our work.
Tristan Kennedy (PhD, 2019-2023)
Christian Westrip (PhD, 2018-2022)
Eline Hendrix (PhD, 2016-2020)
James Bundred (Intercalating medical student, 2017)
Charlotte Hall (PhD, 2015-2019)
Charlotte Eaton (PhD, 2014-2018)
Athanasios Ploumakis (PhD, 2013-2017)
Tianshu Feng (PhD, 2010-2014)
Naseeb Malhi (MRes, 2015)
Hasaam Uldin (visiting medical student, 2015)
Sumayya Iqbal (MSc, 2014)
We welcome enquiries from prospective students, particularly those eligible to apply for funding.