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

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. doi: 10.1093/nar/gkad172 

Fletcher SC, Hall C, Pajusalu S, Wojcik MH, Boora U, Kennedy T, Li C, Oja KT, Hendrix E, Westrip C, Andrijes R, Piasecka SK, Singh M, El-Asrag ME, Ptasinska A, Tillman V, Higgs MR, Carere DA, Beggs AD, Pappas J, Rabin R, Smerdon SJ, Stewart GS, Õunap K, Coleman ML. (2023). Replication stress and abnormal human development caused by impaired protein hydroxylase activity. J Clin Invest. 133:e152784 

Grange LJ, Reynolds JJ, Ullah F, Isidor B, Shearer RF, Latypova X, Baxley RM, Oliver AW, Ganesh AN, Cooke SL, Jhujh SS, McNee GS, Hollingworth R, Higgs MR, Natsume T, Khan T, Martos-Moreno GÁ, Chupp S, Mathew CG, Parry D, Simpson MA, Nahavandi N, Yüksel Z, Drasdo M, Kron A, Vogt P, Jonasson A, Seth SA, Gonzaga-Jauregui C, Brigatti KW, Stegmann APA, Kanemaki M, Josifova D, Uchiyama Y, Oh Y, Morimoto A, Osaka H, Ammous Z, Argente J, Matsumoto N, Stumpel CTRM, Taylor AMR, Jackson AP, Bielinsky A-K, Mailand N, Le Caignec C, Davis EE, Stewart GS. (2022). Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature Comms. 13:6664 

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) 

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 

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 SF3B1K700E mutation induces a BRCA-like cellular phenotype that is vulnerable to treatment with synthetically lethal small molecule inhibitors. Cancer Res. 82:819-830 

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 Comms. 12:6313 

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) 

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 Comms. 12:1626 

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 Comms. 11:4287 

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 Comms. 11:3951 

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 

Taylor AMR, Rothblum-Oviatt C, Ellis NA, Hickson ID, Meyer S, Crawford TO, Smogorzewska A, Pietrucha B, Weemaes C, Stewart GS. (2019). Chromosome instability syndromes. Nature Rev Dis Primers. 5:64. Invited review 

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 

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)



Professor Grant Stewart


  • Dr. Satpal Jhujh
  • Dr. Marcos Rios Garcia
  • Dr. Anoop Chauhan


  • Beth Woodward

Technical staff:

  • Anil Ganesh