Prof Martin Bushell - RNA and Translational Control in Cancer

Introduction

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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:
UKRI MR Council-Logo Horiz-RGB    UKRI BBSR Council-Logo Horiz-RGB

Lab Report

icon Bushell 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; 9: 532.

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; 340: 82-5. 

Biography

Education and qualifications

1999: DPhil, University of Sussex
1993: 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

2020

Bader AS, Bushell M. DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci. Cell Death Dis. 2020; 11: 280

Bader AS, Hawley BR, Wilczynska A, Bushell M. The roles of RNA in DNA double-strand break repair. Br J Cancer. 2020; 122: 61323 

2019

Meijer HA, Schmidt T, Gillen SL, Langlais C, Jukes-Jones R, de Moor CH, Cain K, Wilczynska A, Bushell M. DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity. Nucleic Acids Res. 2019; 47: 8224-8238

Skalka G, Hall H, Somers J, Bushell M, Willis A, Malewicz M. Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionising radiation. Cell Cycle. 2019; 18: 963-975

Waldron JA, Tack DC, Ritchey LE, Gillen SL, Wilczynska A, Turro E, Bevilacqua PC, Assmann SM, Bushell M, Le Quesne J. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity. Genome Biol. 2019; 20: 300.

Wilczynska A, Gillen SL, Schmidt T, Meijer HA, Jukes-Jones R, Langlais C, Kopra K, Lu WT, Godfrey JD, Hawley BR, Hodge K, Zanivan S, Cain K, Le Quesne J, Bushell M. eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR. Genome Biol. 2019; 20: 262.

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; 9: 644

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; 9: 532.

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;

2017

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. 2017; 45: 2809–2828

Hawley BR, Lu WT, Wilczynska A, Bushell M. The emerging role of RNAs in DNA damage repair. Cell Death Differ. 2017; 24: 580-587

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; 27: 638-650

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; 6: 1768–1783

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). Curr Biol. *corresponding author. 2017; 27: 3302-3314.e6

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*.
Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease. Cell Death Differ. 2016; 23:  11521164 *corresponding author

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. Diabetologia. 2016; 59: 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: 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; 157: 4246–4256

Lab Members

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Postdoctoral Scientists

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

Principal Scientific Officers

June Munro
Craig Nourse

PhD Students

Aldo Bader
Adrianna Dabrowska
Sarah Gillen (University of Leicester)
Bashir Mohamed
George Skalka (MRC Technology/ University of Leicester)
Peter Walsh

Research

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Read more about the Research Groups working at the Beatson Institute.

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Seminars

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

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