Professor Grant Stewart PhD

Professor Grant Stewart

Institute of Cancer and Genomic Sciences
Professor of Cancer Genetics

Contact details

Telephone
+44 (0)121 414 9168
Fax
+44 (0)121 414 4486
Email
g.s.stewart@bham.ac.uk
Address
IBR West Extension, First Floor
College of Medical and Dental Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

Defective repair of DNA damage is the most frequent underlying cause of genetic instability and cancer development. My 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 my 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 lead 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 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: 2006-2011 (Current post: Post-Doctoral Researcher at Astra Zeneca)
  • Natalie Forrester: 2007-2011 (Current post: Clinical Research Scientist, Birmingham Regional Department of Cytogenetics)
  • Anoushka Thomas: 2008-2012 (Current post: Medical writing)
  • Rakesh Patel: 2008-2012 (Current post: Unknown)
  • Edward Miller: 2007-2013 (Part time) (Current post: Research Associate at the University of Warwick)
  • Ellis Ryan: 2011-2015 (Current post: Unknown)

If you are interested in studying any of these subject areas please contact Grant on the contact details above, or for any general doctoral research enquiries, please email: dr@contacts.bham.ac.uk or call +44 (0)121 414 5005.

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.
  • Understanding how histone methylation functions to prevent DNA damage-induced replication catastrophe.
  • Discovering novel proteins that play a role in maintaining genome stability.

Other activities

  • Action for A-T Research Advisory Committee (2015)
  • Editorial Board for Oncogene (2013)
  • Editorial Board for DNA Repair (2010)

Publications

Stewart GS**, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AMR, Durocher D**. (2009) The gene mutated in the RIDDLE syndrome mediates a ubiquitin-dependent signalling cascade at sites of DNA damage. Cell 136:420–434 (** Corresponding author)

Noon AT, Shibata A, Rief N, Löbrich M, Stewart GS, Jeggo PA, Goodarzi AA. (2009). 53BP1-dependent robust, localized KAP-1 phosphorylation is essential for heterochromatic DNA double strand break repair. Nat. Cell Biol. 12:177-84.

Zlatanou A, Despras E, Braz-Petta T, Boubakour-Azzouz I, Pouvelle C, Stewart GS, Nakajima S, Yasui A, Ishchenko AA, Kannouche PL. (2011). A novel pathway involving hMsh2-hMsh6 complex, mono-ubiquitinated PCNA and pol eta in response to oxidative DNA damage in human cells. Mol Cell. 43:649-662.

Polo SE, Blackford AN, Chapman JR, Baskcomb L, Gravel S, Rusch A, Thomas A, Blundred R, Smith P, Dobner T, Taylor AMR, Turnell AS, Stewart GS, Grand RJA, Jackson SP. (2012). Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair. Mol Cell. 45:505-16.

Tikoo S, Madhavan V, Miller ES, Arora P, Zlatanou A, Modi P, Townsend K, Stewart GS**, Sengupta S**. (2013). Ubiquitin-dependent recruitment of the Bloom syndrome helicase in response to replication stress is required to suppress homologous recombination. EMBO J. 32:1778-92 (** Corresponding author)

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)

Polo SE, Blackford AN, Chapman JR, Baskcomb L, Gravel S, Rusch A, Thomas A, Blundred R, Smith P, Dobner T, Taylor AMR, Turnell AS, Stewart GS, Grand RJA, Jackson SP. (2012). Regulation of DNA-end resection by hnRNPU-like proteins promotes DNA double-strand break signaling and repair. Mol Cell. 45:505-16.

Byrd PJ, Srinivasan V, Last JI, Smith A, Biggs B, Carney EF, Exley E, Abson C, Stewart GS, Izatt L, Taylor AMR. (2012). Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia. Br. J. Cancer 106:262-8.

Ogi T, Walker S, Stiff T, Hobson E, Limsirichaikul S, Carpenter G, Prescott K, Suri M, Byrd PJ, Matsuse M, Mitsutake N, Nakazawa Y, Vasudevan P, Barrow M, Stewart GS, Taylor AMR, O'Driscoll M, Jeggo PA. (2012). Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genet. 8(11):e1002945.

Tikoo S, Madhavan V, Miller ES, Arora P, Zlatanou A, Modi P, Townsend K, Stewart GS**, Sengupta S**. (2013). Ubiquitin-dependent recruitment of the Bloom syndrome helicase in response to replication stress is required to suppress homologous recombination. EMBO J. 32:1778-92 (** Corresponding author)

Bohgaki M, Bohgaki T, El Ghamrasni S, Srikumar T, Maire G, Panier S, Fradet-Turcotte A, Stewart GS, Raught B, Hakem A, Hakem R. (2013). RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks. Proc Natl Acad Sci U S A. 110:20982-7

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. Aug 2014 [Epub ahead of print].

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)

Zlatanou A, Sabbioneda S, Miller ES, Greenwalt A, Aggathanggelou A, Maurice MM, Lehmann AR, Stankovic T, Reverdy C, Colland F, Vaziri C, Stewart GS. (2015). USP7 is essential for maintaining Rad18 stability and DNA damage tolerance. Oncogene. (In press).