Martin Bushell - RNA and Translational Control in Cancer

Introduction

martin bushell

The dysregulation of protein synthesis in the tumour clone and the supporting stroma is essential for the delivery of oncogenic gene programmes that allow the establishment of both the intracellular and extracellular environments. This is driven by two fundamental post-transcriptional processes. First, hyperactivation of the eIF4F translation initiation complex results in the specific upregulation of oncogenic mRNAs. Secondly, a fundamental shift within tRNA pools promotes oncogenic gene expression programmes by altering the protein synthesis landscape. Recent data from our group and others show that these two processes are coordinated by a number of distinct regulatory RNA-binding complexes and suggest that there is cross-talk between these key steps of the translation process. Our current hypothesis is that these complexes control and connect all post-transcriptional stages of the mRNA lifecycle, from selection, through decoding, to turnover.

The balance of expressed tRNA and codon usage of oncogenic mRNAs that are sensed by these complexes represent a targetable axis of the malignant phenotype, which could be explored therapeutically if mechanistic understanding was available.

The research in our laboratory focuses on understanding how RNA-binding protein complexes, tRNA abundance and codon optimality dictate oncogenic protein production in a coordinated manner. We employ biochemical, biophysical and computational methods to address these questions. We are interested in how the changing tumour environment results in the redeployment of mRNA-binding complexes that control the balance between upregulation of protein translation and mRNA turnover and translational silencing. These mechanistic insights drive our endeavours in designing assays and drug discovery pipelines to target the heart of tumour cell biology.

 
Other funding:
MRC logoBBSRC logo

Lab Report

Key Publications

Lu WT, Hawley BR, Skalka GL, Baldock RA, Smith EM, Bader AS, Malewicz M, Watts FZ, Wilczynska A, Bushell M. Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair. Nat Commun. 2018 Feb 7;9(1):532. doi: 10.1038/s41467-018-02893-x.

Meijer HA, Kong YW, Lu WT, Wilczynska A, Spriggs RV, Robinson SW, Godfrey JD, Willis AE, Bushell M. Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science. 2013 Apr 5;340(6128):82-5. doi: 10.1126/science.1231197.

Biography

Education and qualifications

1996: DPhil, University of Sussex
1991: BSc, Biochemistry (Honours), University of Sussex

Appointments

2018-present: Senior Group Leader, CRUK Beatson Insitute, Glasgow
2018-present: Honorary Professor, University of Leicester
2011-2018: Deputy Director, MRC Toxicology Unit
2014-2018: Professor, Biochemistry Department, University of Leicester
2010-2015: MRC Senior Fellow, Group Leader MRC Toxicology Unit, Leicester
2011-2014: Reader, Biochemistry Department, University of Leicester
2005-2010: BBSRC David Phillips Fellow, School of Pharmacy, Nottingham University
2004-2004: Wellcome Trust ViP Fellow, University of Leicester
2003-2003: Wellcome Trust Travelling Fellow, University of Leicester
2001-2002: Wellcome Trust Travelling Fellow, Stanford University, CA, USA
1999-2000: Postdoctoral Fellow, Prof. M. Clemens, London

Recent Publications

2018

Godfrey JD, Morton JP, Wilczynska A, Sansom OJ, Bushell MD. MiR-142-3p is downregulated in aggressive p53 mutant mouse models of pancreatic ductal adenocarcinoma by hypermethylation of its locus. Cell Death Dis. 2018 May 29;9(6):644. doi: 10.1038/s41419-018-0628-4.

Lu WT, Hawley BR, Skalka GL, Baldock RA, Smith EM, Bader AS, Malewicz M, Watts FZ, Wilczynska A, Bushell M. Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair. Nat Commun. 2018 Feb 7;9(1):532. doi: 10.1038/s41467-018-02893-x.

Marini A, Rotblat B, Sbarrato T, Niklison-Chirou MV, Knight JRP, Dudek K, Jones C, Bushell M, Knight RA, Amelio I, Willis AE, Melino G. TAp73 contributes to the oxidative stress response by regulating protein synthesis. Proc Natl Acad Sci U S A. 2018 May 29. pii: 201718531. doi: 10.1073/pnas.1718531115. [Epub ahead of print]

2017

Hawley BR, Lu WT, Wilczynska A, Bushell M. The emerging role of RNAs in DNA damage repair. Cell Death Differ. 2017

Bastide A, Peretti D, Knight JR, Grosso S, Spriggs RV, Pichon X, Sbarrato T, Roobol A, Roobol J, Vito D, Bushell M, von der Haar T, Smales CM, Mallucci GR, Willis AE. RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3. Curr Biol. 2017

Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M, Mallucci GR. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain. 2017

Chernova T, Murphy FA, Galavotti S, Sun X-M, Powley IR, Grosso S, Schinwald A, Zacarias-Cabeza J, Dudek KM, Dinsdale D, Le Quesne J, Bennett J, Nakas A, Greaves P, Poland CA, Donaldson K, Bushell M*, Willis AE*, MacFarlane M*. Long-Fibre Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumour Suppressor Gene Cdkn2a (Ink4a/Arf). In press, Curr Biol. *corresponding author

2016

Chernova T, Sun XM, Powley IR, Galavotti S, Grosso S, Murphy FA, Miles GJ, Cresswell L, Antonov AV, Bennett J, Nakas A, Dinsdale D, Cain K, Bushell M*, Willis AE*, MacFarlane M*. *corresponding author
Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease. Cell Death Differ. 2016.

Martin-Gronert MS, Fernandez-Twinn DS, Bushell M, Siddle K, Ozanne SE. Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition. Martin-Gronert MS, Fernandez-Twinn DS, Bushell M, Siddle K, Ozanne SE. Diabetologia. 2016 59(6):1266-75.

Hall AE, Lu WT, Godfrey JD, Antonov AV, Paicu C, Moxon S, Dalmay T, Wilczynska A, Muller PA, Bushell M. The cytoskeleton adaptor protein ankyrin-1 is upregulated by p53 following DNA damage and alters cell migration. Cell Death Dis. 2016 7:e2184.

Sbarrato T, Horvilleur E, Pöyry T, Hill K, Chaplin LC, Spriggs RV, Stoneley M, Wilson L, Jayne S, Vulliamy T, Beck D, Dokal I, Dyer MJ, Yeomans AM, Packham G, Bushell M, Wagner SD, Willis AE. A ribosome-related signature in peripheral blood CLL B cells is linked to reduced survival following treatment. Cell Death Dis. 2016 7(6):e2249.

Alfaradhi MZ, Kusinski LC, Fernandez-Twinn DS, Pantaleão LC, Carr SK, Ferland-McCollough D, Yeo GS, Bushell M, Ozanne SE. Maternal obesity in pregnancy developmentally programs adipose tissue inflammation in young, lean male mice offspring. Endocrinology. 2016 :en20161314.

Fletcher CE, Godfrey JD, Shibakawa A, Bushell M, Bevan CL. A novel role for GSK3β as a modulator of Drosha microprocessor activity and MicroRNA biogenesis. Nucleic Acids Res. 2016

2015

Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, Jones C, Radulescu S, Huels DJ, Myant KB, Dudek KM, Casey HA, Scopelliti A, Cordero JB, Vidal M, Pende M, Ryazanov AG, Sonenberg N, Meyuhas O, Hall MN, Bushell M, Willis AE, Sansom OJ. mTORC1 mediated translational elongation is limiting for intestinal tumour initiation and growth. Nature, 2015 517 497-500.

Lu WT, Bushell M. Old case, new leads: miRNA links Kaposi's sarcoma-associated herpesvirus with sepsis. Cell Death Dis. 2014 5:e1560.

Mura M, Hopkins TG, Michael T, Abd-Latip N, Weir J, Aboagye E, Mauri F, Jameson C, Sturge J, Gabra H, Bushell M, Willis AE, Curry E, Blagden SP. LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression. Oncogene. 2015 34(39):5025-36.

Nolte-'t Hoen EN, Van Rooij E, Bushell M, Zhang CY, Dashwood RH, James WP, Harris C, Baltimore D. The role of microRNA in nutritional control. J Intern Med. 2015 278:99-109.

Somers J, Wilson LA, Kilday JP, Horvilleur E, Cannell IG, Poyry TAA, Cobbold LC, Kondrashov A, Knight JRP, Puget S, Grill J, Grundy RG, Bushell M, Willis AE. A common polymorphism in the 5'UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy. Genes Dev. 2015 29(18):1891-6.

2014

Horvilleur E, Sbarrato T, Hill K, Spriggs RV, Screen M, Goodrem PJ, Sawicka K, Chaplin LC, Touriol C, Packham G, Potter KN, Dirnhofer S, Tzankov A, Dyer MJ, Bushell M, Macfarlane M, Willis AE. A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma. Leukemia, 2014, 28(5):1092-102

King HA, Cobbold LC, Pichon X, Pöyry T, Lindsay A, Wilson LA, Booden H, Jukes-Jones R, Cain K, Lilley KS, Bushell M, Willis AE. Remodelling of a polypyrimidine tract binding protein complex during apoptosis activates cellular IRESs. Cell Death Differ. 2014, 21(1):161-71

Kamenska A. Lu W-T. Kubacka D. Broomhead H. Minshall N. Bushell M, Standart N. Human 4E-T represses translation of bound mRNAs and enhances silencing of microRNA-target mRNAs. Nucleic Acids Res. 2014, 42(5):3298-313.

Dhiraj DK, Chrysanthou E, Mallucci GR, Bushell M. miRNAs-19b, -29b-2* and -339-5p show an early and sustained up-regulation in ischemic models of stroke. PLoS On. 2013, 8(12):e83717

Lu WT, Wilczynska A, Smith E, Bushell M. The diverse roles of the eIF4A family: you are the company you keep. Biochem Soc Trans. 2014, 42(1):166-72

Fernandez-Twinn DS, Alfaradhi MZ, Martin-Gronert MS, Duque-Guimaraes DE, Piekarz A, Ferland-McCollough D, Bushell M, Ozanne SE. Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms. Molecular Metabolism, 2014 3(3):325-33.

Meijer HA, Smith EM, Bushell M. Regulation of miRNA strand selection: follow the leader?
Biochem Soc Trans. 2014, 42(4):1135-40.

Lab Members

Associate Scientist

Ania Wilczynska

Post-docs

Nour Benbahouche (CRUK Programme)
Holly Hall (BBSRC)
Ridhima Lal (MRC)
Tobias Schmidt (BBSRC)
Ewan Smith
Joe Waldron (CRUK Programme)

Scientific Officer

June Munro

PhD Students

Aldo Bader
Adrianna Dabrowska
Sarah Gillen
Bashir Mohamed

Research

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Seminars

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Find out more about our seminars including our Distinguished Seminar Programme.

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