Genome Stability and Human Disease

G Stewart Group Website banner of DNA damage images

Group leader: Professor Grant Stewart


Defective repair of DNA damage is the most frequent underlying cause of genetic instability and cancer development. Our 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.

Our research group

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 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 the proteins involved in regulating the DDR 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.

A large proportion of the research ongoing in 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, characterising human gene mutations and their impact on the DDR and identifying novel human disease genes associated with genome instability and a predisposition to the development of cancer.Micronuclei formation diagram as described above

Current projects

1. Understanding how the ubiquitin system controls repair of damaged DNA.

2. Identification and characterisation of novel proteins involved in regulating the cellular response to DNA damage.

3. Identifying novel genes mutated in human syndromes associated with the defective repair of DNA damage.

4. Understanding how viruses subvert the host cell DNA damage response pathways.

Recent publications

  • 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
  • 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
  • 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)
  • 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)
  • 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
  • Bohgaki T, Bohgaki M, Cardosos R, Panier S, Stewart GS, Sanchez O, Durocher D, Hakem A, Hakem R. (2011). Genomic instability, defective spermatogenesis, immunodeficiency and cancer in a mouse model of the RIDDLE syndrome. PLOS Genet. 7: e1001381.5.
  • 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)
  • Stewart GS**, Stankovic T, Byrd PJ, Wechsler T, Miller ES, Huissoon A, Drayson MT, West SC, Elledge SJ, Taylor AM. (2007). RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proc Natl Acad Sci USA. 104:16910-5. (** Corresponding author)
  • Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ. (2003). MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421:961-6.



Professor Grant Stewart


  • Dr. John Reynolds
  • Dr. Rob Hollingworth
  • Dr. Louise Lindbaek
  • Dr. Danxu Liu


  • Satpal Jhujh
  • Rachel Mottram

Technical staff:

Audrey Vernet