Professor Grant Simon Stewart Bsc (Hons) PhD

Department of Cancer and Genomic Sciences
Professor of Cancer Genetics

Contact details

Telephone: +44 (0)121 414 9168
Email: g.s.stewart@bham.ac.uk
Twitter: @GS_Lab_Bham

Address: Department of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

Professor Grant Stewart is a Professor of Cancer Genetics in the Department of Cancer and Genomic Sciences.

Defective repair of DNA damage is the most frequent underlying cause of genetic instability and cancer development. Professor Stewart's research focuses on understanding how the cell detects and repairs damage to its DNA and how defects in this process contribute to the development of human disease. In this respect Professor Stewart's laboratory has had a long-standing interest in rare human diseases associated with defective DNA repair and/or abnormal DNA replication such as Ataxia-Telangiectasia, Fanconi Anaemia, Seckel Syndrome and Microcephalic Primordial Dwarfism.

Studying these rare human diseases has provided a wealth of invaluable information about how defects affecting the cellular DNA damage response (DDR) contribute to neuro-degeneration, abnormal brain development, immune system dysfunction, growth failure, infertility and cancer development. Importantly, our in depth understanding of the DDR is now being utilised therapeutically and has led to the generation of highly specific inhibitors that are being successfully used to selectively target DNA repair deficient tumours.

Qualifications

2015, Professor of Cancer Genetics, University of Birmingham.
2012-2015, Reader in Cancer Genetics, University of Birmingham.
2009-2012, CR-UK Senior Research Fellow, University of Birmingham.
2005-2011, CR-UK Career Development Fellow, University of Birmingham.
2000, Ph.D. University of Birmingham, UK.
1996, BSc (Hons) - First Class, University of Bristol, UK.

Biography

Professor Grant Stewart received his first degree in Cellular and Molecular Pathology at the University of Bristol (1996). He subsequently joined the laboratory of Professor Malcolm Taylor at the University of Birmingham to do a Ph.D. studying the heterogeneity of the chromosomal instability syndrome, Ataxia-Telangiectasia (A-T), and the role of the ATM (Ataxia-Telangiectasia Mutated) gene in sporadic leukaemia. During the course of his Ph.D., he identified mutations in DNA double strand break (DSB) gene, hMRE11, also contributed to the development of a syndrome similar to A-T (A-T-like disorder or ATLD), firmly establishing a genetic link between the hMre11 DSB repair complex and ATM.

Continuing his growing interest in the cellular response to DNA damage, he moved in 2002, with a European Molecular Biology Organisation (EMBO) Long Term Fellowship, to the laboratory of Professor Stephen Elledge at Baylor College of Medicine (Houston, Texas). Whilst at Baylor, he identified a novel DNA double strand break repair protein called Mediator of DNA Damage Checkpoint 1 (MDC1) and demonstrated it played a role in recruiting other DSB responsive proteins to the sites of DNA breaks to facilitate repair and cell cycle checkpoint activation.

In 2005 Professor Grant Stewart moved back to the University of Birmingham with a CR-UK Career Development Fellowship to start up his own laboratory. During the course of this fellowship, his group identified a novel human immunodeficiency syndrome associated with defective repair of DNA DSBs called RIDDLE syndrome. Through a collaboration his laboratory was able to identify the gene mutated in RIDDLE syndrome as RNF168 and that the encoded protein facilitates the recruitment of DSB repair proteins, such as 53BP1 and BRCA1, to sites of DNA damage by promoting relaxation of the chromatin structure surrounding the break.

In 2009 Professor Grant Stewart received the Lister Institute Research Prize for his work on human DNA repair deficiency disorders. In 2011 Professor Grant Stewart was awarded a CR-UK Senior Fellowship to continue his research into understanding how the cell detects and repairs damage to its DNA and how defects in this process contribute to human disease and cancer development.

Current research in the Stewart laboratory focuses on the identification and functional characterisation of novel human disease genes associated with defects in DNA repair and/or abnormal DNA replication. The Stewart group has a long-standing interest in understanding how the ATM/ATR-dependent DNA damage response is regulated, how ubiquitin controls DNA double strand break repair and the link between the Fanconi Anaemia pathway and replication stress.

Teaching

BMedSci Year 2 (Cell Cycle Regulation)
BMedSci Year 2 (Advanced Molecular & Experimental Genetics)
BMedSci Year 2 (Cancer and Stratified Medicine)
BMedSci Year 3 (Cancer Therapy Option)
MBCh.B Year 2 (Cancer: Causes to Cures – Small group teaching)
Msc Clinical Oncology

Postgraduate supervision

Helen Mason (Ph.D): 2006-2011
Natalie Forrester (Ph.D): 2007-2011
Anoushka Thomas (Ph.D): 2008-2012
Rakesh Patel (Ph.D): 2008-2012
Edward Miller (Ph.D): 2007-2013 (Part time)
Ellis Ryan (Ph.D): 2011-2015
Rachel Mottram (Ph.D): 2015-2019
Nafiseh Chalabi Hagkarim (Ph.D): 2015-2019
Ellen Higgs (Ph.D): 2016-2019
Satpal Jhujh (Ph.D): 2016-2020
Laura Grange (Ph.D): 2018-2022
Beth Woodward (MB-Ph.D) 2020-2024

If you are interested in studying any of these subject areas please contact Professor Stewart directly, or for any general doctoral research enquiries, please email mds-gradschool@contacts.bham.ac.uk

Research

Genome instability is a genetic trait that is common to all cancer. Abnormal repair of DNA damage is the most frequent underlying cause of genome instability and probably represents the most important event that contributes to, and in some cases initiates the development of cancer. Therefore, cellular pathways that control the repair of damaged DNA as well as those that regulate cell cycle checkpoints and the apoptotic machinery represent an inherent anti-tumour barrier that must be surpassed for a tumour to develop. The principal focus of the laboratory is to determine how the cell detects and faithfully repairs damage to its DNA. The biochemical pathways involved in this process are collectively termed the DNA damage response (DDR) and consist of those that regulate DNA damage detection, cell cycle checkpoint activation, DNA repair and apoptosis.

Much of our insight about how DDR proteins function and the biological consequences if this fails, has come about from the study of rare inherited human syndromes associated with genome instability and a high prevalence of cancer e.g. Ataxia-Telangiectasia and Fanconi Anaemia. A large proportion of the research on going in the Stewart laboratory centres around understanding how defects in DDR pathways contribute to human disease (which includes providing a genetic diagnosis for patients with a suspected DNA repair deficiency disorder) and identifying novel human disease genes associated with genome instability and a predisposition to the development of cancer.

Current research in the Stewart laboratory:

Identification and characterisation of novel genes within the ATR-dependent DNA damage response pathway that give rise to Seckel Syndrome and Microcephalic Primordial Dwarfism.
Identification and characterisation of novel human disorders caused by mutations in genes that encode proteins involved in DNA replication.
Investigating how different mutations in the ATM-Nbn-Mre11-Rad50 DNA double strand break repair pathway give rise to distinct clinical phenotypes.
Discovering novel proteins that play a role in maintaining genome stability.

ResearchGate Profile

Other activities

Editorial board for Nucleic Acids Research (2021-present)
Editorial Board for Molecular and Cellular Biology (2017-2020)
Global A-T Family Data Platform (A-T Children’s Project) Scientific and Medical Advisory Board (2016-present)
Action for A-T Research Advisory Committee (2015-present)
Editorial Board for Oncogene (2013-present)
Editorial Board for DNA Repair (2010-present)

Publications

Thomas A, Perry T, Berhane S, Oldreive C, Zlatanou A, Williams LR, Weston VJ, Stankovic T, Kearns P, Pors K, Grand RJ, Stewart GS. (2014). The dual acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53. Oncogene. 34:3336-48.

Murray JE, van der Burg M, IJspeert H, Carroll P, Wu Q, Ochi T, Leitch A, Miller ES, Kysela B, Jawad A, Bottani A, Brancati F, Cappa M, Cormier-Daire V, Deshpande C, Faqeih EA, Graham GE, Ranza E, Blundell TL, Jackson AP**, Stewart GS**, Bicknell LS. (2015). Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am J Hum Genet. 96:412-24. (** Corresponding author)

Higgs MR, Reynolds JJ, Winczura A, Blackford AN, Borel V, Miller ES, Zlatanou A, Nieminuszczy J, Ryan EL, Davies NJ, Stankovic T, Boulton SJ, Niedzwiedz W, Stewart GS. (2015). BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks. Mol Cell. 59:462-77.

Zlatanou A, Sabbioneda S, Miller ES, Greenwalt A, Aggathanggelou A, Maurice MM, Lehmann AR, Stankovic T, Reverdy C, Colland F,Vaziri C, Stewart GS. (2016). USP7 is essential for maintaining Rad18 stability and DNA damage tolerance. Oncogene. 35:965-76.

Harley ME, Murina O, Leitch A, Higgs MR, Bicknell LS, Yigit G, Blackford AN, Zlatanou A, Mackenzie K, Reddy K, Halachev M, McGlasson S, Reijns MAM, Fluteau A, Martin C-A, Sabbioneda S, Elcioglu NH, Altmüller J, Thiele H, Greenhalgh L, Chessa L, Maghnie M, Salim M, Bober MB, Nürnberg P, Jackson SP, Hurles ME, Wollnik B, Stewart GS**, Jackson AP**. (2016). The primordial dwarfism gene TRAIP promotes DNA damage response during genome replication. Nature Genet. 48:36-43(** Corresponding author)

Guturi KKN, Bohgaki M, Bohgaki T, Srikumara T, Ng D, Kumareswaran R, El Ghamrasni S, Jeon J, Patel P, Saad Eldin M, Bristow R, Cheung P, Stewart GS, Raught B, Hakem A, Hakem R. (2016). RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation. Nature Commun. 7:12638

Clarke TL, Sanchez-Bailon MP, Chiang K, Reynolds JJ, Herrero-Ruiz J, Bandeiras TM, Matias PM, Maslen SL, Skehel JM, Stewart GS, Davies CC. (2017). PRMT5-mediated methylation of the TIP60 coactivator RUVBL1 is a key regulator of homologous recombination. Mol Cell. 65:900-916

Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE, Papadopoulos DK, Leitch A, Murina O, Tarnauskaitė Ž, Wessel SR, Zlatanou A, Vernet A, Kriegsheim A, Mottram RMA, Logan CV, Bye H, Li Y, Brean A, Maddirevula S, Challis RC, Skouloudaki K, Almoisheer A, Alsaif HS, Amar A, Prescott NJ, Bober MB, Duker A, Faqeih E, Seidahmed MZ, Tala SA, Alswaid A, AhmedS, Al-Aama JY, Altmüller J, Balwi MA, Brady AF, Chessa L, Cox H, Fischetto R, Heller R, Henderson BD, Hobson E, Nürnberg P, Percin EF, Peron S, Spaccini L, Quigley AJ, Thakur S, Wise CA, Yoon G, Alnemer M, TomancakP, Yigit G, Taylor AMR, Reijns MAM, Simpson MA, Cortez D, Alkuraya FS, Mathew CG, Jackson AP, Stewart GS. (2017). Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature Genet. 49:537-549

Agathanggelou A, Smith E, Davies NJ, Kwok M, Zlatanou A, Oldreive CE, Mao J, Da Costa D, Yadollahi S, Perry T, Kearns P, Skowronska A, Yates E, Parry H, Pratt G, Moss P, Taylor AMR, Stewart GS**, Stankovic T.** (2017). USP7 inhibition alters homologous recombination repair and targets CLL cells independent of ATM/p53 functional status. Blood. 130:156-166 (** Corresponding author)

Higgs MR, Sato K, Reynolds JJ, Begum S, Bayley R, Goula A, Vernet A, Paquin KL, Skalnik DG, Kobayashi W, Takata M, Howlett NG, Kurumizaka H, Kimura H, Stewart GS. (2018). Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2. Mol Cell. 71:25-41

Burrage LC, Reynolds JJ, Baratang NV, Phillips JB, Wegner J, McFarquhar A, Higgs MR, Christiansen AE, Lanza D, Seavitt J, Jain M, Li X,Parry D, Raman V, Chitayat D, Chinn IK, Bertuch AA, Karaviti L, Schlesinger AE, Earl D, Bamshad M, Savarirayan R, Doddapaneni H, Muzny D, Jhangiani SN, Eng C, Gibbs RA, Bi W, Emrick L, Rosenfeld JA, Postlethwait J, Westerfield M, Dickinson M, Beaudet A, Ranza E, Huber C, Cormier-Daire V, Shen W, Mao R, Heaney JD, Orange JS, University of Washington Center for Mendelian Genomics, Undiagnosed Diseases Network, Bertola D, Yamamoto G, Baratela WAR, Butler MG, Ali A, Adeli M, Cohn DH, Krakow D, Jackson AP, Lees M, Offiah AC, Carlston CM, Carey JC, Stewart GS**, Bacino CA**, Campeau PM**, Lee B.** (2019). Biallelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. Am J Hum Genet. 104:422-438 (** Senior author)

Daza-Martin M, Starowicz K, Jamshad M, Tye S, Ronson GE, MacKay HL, Chauhan AS, Walker AK, Stone HR, Beesley JFJ, Coles JL, Garvin AJ, Stewart GS, McCorvie T, Zhang X, Densham RM, Morris JR. (2019). Phosphorylation and isomerization regulation of BRCA1-BARD1 promotes replication fork protection. Nature 571:521-527

Zarrizi R, Higgs MR, Voßgröne K, Rossing M, Bertelsen B, Bose M, Nedergaard Kousholt A, Rösner H, The Complexo Network, Ejlertsen B, Stewart GS, Cilius Nielsen F, Sørensen CS (2020). Germline RBBP8 variants associated with early onset breast cancer compromise replication fork stability. J. Clin Invest 130:4069-4080

Zhang J, Bellani MA, James R, Pokharel D, Pratto F, Zhang Y, Reynolds JJ, McNee GS, Jackson AP, Camerini-Otero RD, Stewart GS, Seidman MM. (2020). DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain. Nature Commun. 11:3951

Faramarz A, van Schie J, Balk J, Stewart GS, Oostra A, Rooimans M, Parish J, De Almedia Estéves C, Dumic K, Barisic I, Diderich K, Pisani F, Ameziane N, Wolthuis R, de Lange J. (2020) DDX11 helicase activity protects against G-quadraplex induced chromosomal breakage and concomitant loss of sister chromatid exchange. Nature Commun. 11:4287

Baxley RM, Leung W, Schmit MM, Matson JP, Oram MK, Wang L, Yin L, Hedberg J, Rogers CB, Harvey AJ, Basu D, Hendrickson EA, Mace EM, Orange JS, Aihara H, Stewart GS, Blair E, Gowen Cook J, Bielinsky AK. (2020). Bi-allelic MCM10 mutations cause telomere shortening with immune dysfunction and cardiomyopathy. Nature Commun. 12:1626

Blakemore D, Vilaplana N, Almaghrabi R, Gonzalez E, Moya M, Murphy G, Gambus A, Petermann E, Stewart GS**, Garcia P.** (2021) MYBL2 and ATM prevent replication stress in pluripotent stem cells. EMBO Reports 22:e51120 (** Senior author)

Sanchez-Bailon MP, Choi S-Y, Dufficy ER, Sharma K, McNee GS, Gunnell E, Chiang K, Sahay D, Maslen S, Stewart GS, Skehel JM, Davies CC. (2021). Arginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair. Nature Commun. 12:6313

Lappin KM, Barros EM, Jhujh SS, Irwin G, Liberante F, Latimer C, Wilson M, Mills KI, Harkin DP, Stewart GS, Savage KI. (2022). The cancer associated SF3B1^K700E mutation induces a BRCA-like cellular phenotype that is vulnerable to treatment with synthetically lethal small molecule inhibitors. Cancer Res 82:819-830

Abu-Libdeh B, Jhujh SS, Dhar S, Sommers JA, Datta A, Longo GMC, Grange LJ, Reynolds JJ, Cooke SL, McNee GS, Hollingworth R, Woodward BL, Ganesh AN, Smerdon SJ, Nicolae CM, Durlacher-Betzer K, Molho-Pessach V, Abu-Libdeh A, Meiner V, Moldovan G-L, Roukos V, Harel T, Brosh Jr. RM, Stewart GS. (2022). RECON Syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1. J Clin Invest. 132:e147301

Bayley R, Borel V, Moss RJ, Sweatman E, Ruis P, Ormrod A, Goula A, Mottram RMA, Stanage T, Hewitt G, Saponaro M, Stewart GS**, Boulton SJ**, Higgs MR**. (2022). H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ. Mol Cell.82:1924-1939 (** Corresponding author)

Patel PS, Algounesh A, Krishnan R, Reynolds JJ, Nixon KCJ, Krishnan R, Hao J, Lee J, Feng Y, Fozil C, Stanic M, Yerlici T, Su P, Soares F, Liedtke E, Prive G, Baider GD, Angel Pujana M, Mekhail K, Hansen He H, Hakem A, Stewart GS, Hakem R. (2023). Excessive transcription-replication conflicts are a vulnerability of BRCA1-mutant cancers. Nucleic Acids Res. 51:4341-4362

Nieminuszczy J, Martin PR, Broderick R, Krwawicz J, Kanellou A, Mocanu C, Bousgouni V, Smith C, Wen K-K, Woodward BL, Bakal C, Shackley F, Aguilera A, Stewart GS, Vyas YM, Niedzwiedz W. (2023). Actin nucleators safeguard replication forks by limiting nascent strand degradation. Nucleic Acids Res. 51:6337-6354

Krishnan R, Lapierre M, Gautreau B, El Ghamrasni S, Patel PS, Nixon KCJ, Yerlici T, Guturi K, St-Germain J, Mateo F, Algouneh A, Earnshaw R, Miller J, Khosraviani N, Fozil C, Penn A, Ho B, Sanchez O, Brown G, Reynolds JJ, Mekhail K, Raught B, Pujana M, Stewart GS, Hakem A, Hakem R. (2023). RNF8 regulates R-loop resolution to prevent transcription-dependent DNA damage and is a vulnerability for BRCA1-mutant breast cancer. Nucleic Acids Res. 51:10484-10505.

Cvetkovic MA, Passaretti P, Butryn A, Reynolds-Winczura A, Kingsley G, Skagia A, Fernandez-Cuesta C, Poovathumkadavil D, George R, Chauhan AS, Jhujh SS, Stewart GS, Gambus A, Costa A. (2023). The structural mechanism of dimeric DONSON in replication helicase activation. Mol Cell. 83:4017-4031.

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