Genome Stability Lab (GSL)
Research in the group aims to better understand how cells maintain stable genomes and how genomically instable cancers can be detected and targeted in novel ways. Specifically, we are working on two topics to improve strategies of preventing and treating diseases of unmet need in the future.
1. How do ubiquitylation pathways regulate the DNA damage response and associated processes? To address this, we are integrating cell biology, biochemistry, bioinformatics and high through-put/high-content quantitative microscopy/microarray techniques. The importance of ubiquitylation and DNA damage response pathways is illustrated by a declining ubiquitin system and accumulating DNA damage giving rise to various human disorders such as cancer and neurodegenerative diseases.
2. Ovarian cancer displays rampant genomic instability and has low long-term survival rates with less than 30 percent of women outliving the disease for more than ten years, mainly due to a lack of early detection methods. We are establishing cutting-edge nanotechnology, cell biology, molecular biology, biochemistry and advanced microscopy methods to develop innovative biohybrid drug-delivery vehicles to detect and target the disease earlier.
María José Cabello (since August 2017)
María José received her PhD in 2016 at the Andalusian Centre of Molecular Biology and Regenerative Biomedice (Seville, Spain). She joined the lab in August 2017 as a postdoctoral researcher to work on the role of SUMO in the DNA damage response.
Elsa Irving (since February 2019)
Elsa received her PhD from the UCL Great Ormond Street Institute of Child Health in 2019. She is now a postdoctoral fellow in collaboration with Dr Josep Forment at AstraZeneca based in the DNA damage response group within oncology. She is working on targeting ubiquitylation factors in tumour cells, in particular in those with homologous repair deficiencies.
Hugh Osborne (since October 2018)
Hugh Osborne obtained a Master’s degree in Pharmacy (MPharm) in 2016 from the University of East Anglia (UEA), with a focus on Medicinal Chemistry. He went on to complete his pre-registration year at the Norfolk & Norwich University Hospital, qualifying as a pharmacist in August 2017. He then worked as a locum pharmacist and as a Blue Book Trainee for the European Commission (Grange, Ireland) before joining the lab in collaboration with Prof. Igor Larrosa's group in September 2018 as a PhD student to work on the development of selected small-molecule inhibitors in the context of the DNA damage response and certain cancer types.
Isabelle Cristine Da Costa (since October 2018)
Isabelle Cristine has a conjoined BSc in Biotechnology from the Federal University of Goias (Brazil) and Michigan State University (USA) and an industrial internship on lung cancer at Abbot/AbbVie Laboratories (USA). She obtained her Master's degree in Biological Sciences in 2018 from the University of Manchester where she worked with haematopoietic stem cells (Dr Valerie Kouskoff's lab) and creation of yeast hybrids with biotechnological applications (Prof. Daniela Delneri's lab). Her current research in the lab focuses on understanding the function and molecular pathways of selected ubiquitin-like modifiers in the DNA damage response and how they are related to prostate cancer.
Konstancja Urbaniak (since September 2018)
Konstancja Urbaniak obtained her Master’s by Research (MRes) in Molecular and Cellular Medicine in 2017 from the University of Bristol where she worked on the correlation between posttranslational modifications and dynamics of microtubules and DNA damage response signalling. In September 2018, she started an A*STAR PhD programme in the group in collaboration with Dr Jim Warwicker’s and Prof. Frank Eisenhaber’s labs. Her research focuses on the systematic identification of SUMO-binding proteins within and beyond the DNA damage response.
Zac Sandy (since October 2019)
Zac Sandy obtained his Master’s degree (MRes) in Cancer Science in 2019 from the University of Birmingham. There he worked in Dr Clare Davies’ lab investigating the roles of arginine modifications in the DNA damage response. In October 2019 he joined the lab as part of a BBSRC CTP studentship in collaboration with Dr Josep Forment’s group at AstraZeneca. His current research focuses on exploring the roles of selected ubiquitin-like modifiers in the DNA damage response.
Melanie Seaton (since October 2019)
Melanie Seaton obtained an integrated Master’s degree in Pharmacology from The University of Manchester in 2019. For her final year project she worked in Prof. Stuart Allan’s lab on the mechanisms of inflammation in vascular dementia. She joined the lab in 2019 as a PhD student to work on the development of cellular micromotors for improved management of ovarian cancer.
Zijuan Wang (since October 2021)
Zijuan received her Master’s degree in Pharmaceutical Chemistry in 2021 from Zhejiang University, China. There, she focused on the exploration of the structure-activity relationships of influenza endonuclease. In October 2021 she joined the lab as a BBSRC DTP student to work on the mapping of weak and transient UBL receptor interactions using tailored photo-crosslinking chemistry.
Jennifer Chandler (since September 2021)
Jenny is completing her integrated MSci degree in Biomedical Sciences at the University of Manchester. She has joined the lab for her final year research project looking into the potential binding and function of SUMO in non-homologous end-joining.
Brett Weller (since October 2021)
Brett gained his Bachelor’s degree in Biochemistry from the University of Bedfordshire in 2021. He has joined the lab for his research project as part of his MRes Biochemistry Master’s degree, focusing on ubiquitin receptors within the DNA damage response.
Caitlin Kyle (June - September 2021)
Caitlin gained her Bachelor’s degree in Biochemistry at the University of Manchester in 2020. She joined the lab for her research project on defining novel ubiquitin receptors as part of her Clinical Biochemistry Master’s degree. After this, she joined the NHS Scientist Training Programme in Manchester where she is specialising in Clinical Biochemistry and gaining another Master’s degree in Clinical Science.
Stephenie Purvis (October 2018 - July 2019)
Stephenie gained her Bachelor's degree in Biomedical Science from the University of Kent in 2018. She joined the lab for her research project as part of her MRes Oncology Master's degree. Since leaving, she has been accepted onto the highly competitive NHS Scientific Training Programme in Cambridge where she will not only be specialising in Cancer Genomics but also gaining another Master's degree in Clinicial Science.
Mariam Nasr (September 2017 - May 2018)
Mariam joined the lab and Richard Edmondson's group as an undergraduate student in her final year of her MSci Genetics degree, looking into defects in homologous recombination in ovarian cancer cells.
Publications & preprints
Cabello-Lobato MJ, Schmidt CK*, Cliff MJ*. 1H, 13C, 15N backbone resonance assignment for the 1-164 construct of human XRCC4. Biomolecular NMR Assignments (2021). 15, 389–395. http://link.springer.com/article/10.1007/s12104-021-10035-6
Osborne HC, Irving E, Forment JV, Schmidt CK. E2 enzymes in genome stability: pulling the strings behind the scenes. Trends in Cell Biology (2021). https://doi.org/10.1016/j.tcb.2021.01.009.
Cabello-Lobato MJ, Jenner M, Loch CM, Jackson SP, Wu Q, Cliff MJ, Schmidt CK. Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining. bioRxiv (2021). DOI: 10.1101/2021.01.20.427433.
Sandy Z, da Costa IC, Schmidt CK. More than meets the ISG15: emerging roles in the DNA damage response and beyond. Biomolecules (2020). DOI: 10.3390/biom10111557.
Schmidt CK$, Medina-Sánchez M$, Edmondson RJ, Schmidt OG$. Engineering microrobots for targeted cancer therapies from a medical perspective. Nature Communications (2020). DOI: 10.1038/s41467-020-19322-7. $Co-corresponding authors
Xu H, Medina-Sánchez M$, Zhang W, Seaton M, Brison DR, Edmondson RJ, Taylor SS, Nelson L, Zeng K, Bagley S, Ribeiro C, Restrepo LP, Lucena E, Schmidt CK$, Schmidt OG$. Human spermbots for patient-representative 3D ovarian cancer cell treatment. Nanoscale (2020). DOI: 10.1039/D0NR04488A. $Co-corresponding authors
Osborne HC, Irving E, Schmidt CK. The ubiquitin/UBL drug target repertoire. Trends in Molecular Medicine (2020). DOI: 10.1016/j.molmed.2020.08.009.
Osborne HC, Durie A, Schmidt CK, Larrosa I. C-H borylation: no need to stop for directions. Trends in Chemistry (2020). DOI: 10.1016/j.trechm.2020.07.009.
Da Costa IC & Schmidt CK. Ubiquitin-like proteins in the DNA damage response: the next generation. Essays Biochem. (2020) 1–16.
van den Tempel N, Zelensky AN, Odijk H, Laffeber C, Schmidt CK, Brandsma I, Demmers J, Krawczyk PM, Kanaar R. On the mechanism of hyperthermia-induced BRCA2 protein degradation. Cancers (2019) 11: 97.
Cabello-Lobato MJ, Wang S, Schmidt CK. SAMHD1 sheds moonlight on DNA double-strand break repair. Trends in Genetics (2017) 12: 895-897.
Xi W$, Schmidt CK$, Sanchez S, Gracias DH, Carazo-Salas RE, Butler R, Lawrence N, Jackson SP, and Schmidt OG. Molecular Insights into Division of Single Human Cancer Cells in On-Chip Transparent Microtubes. ACS Nano (2016) 10: 5835–5846. $Co-corresponding authors; highlighted in acs.org (ACS, June 2016) and sciencenews.org (Sciencenews, June 2016).
Schmidt CK$, Galanty Y$, Sczaniecka-Clift M, Coates J, Jhujh S, Demir M, Jackson SP. Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair. Nature Cell Biology (2015) 17: 1458-1470. $Co-first authors
Aymard F, Bugler B, Schmidt CK, Guillou E, Caron P, Briois S, Iacovoni JS, Daburon V, Miller KM, Jackson SP et al. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nat Struct Mol Biol (2014) 21: 366–374.
Knobel PA, Belotserkovskaya R, Galanty Y, Schmidt CK, Jackson SP, Stracker TH. USP28 is recruited to sites of DNA damage by the tandem BRCT domains of 53BP1 but plays a minor role in double-strand break metabolism. Mol Cell Biol (2014) 34: 2062–2074.
Xi W, Schmidt CK$, Sanchez S$, Gracias DH, Carazo-Salas RE, Jackson SP, Schmidt OG. Rolled-up Functionalized Nanomembranes as Three-Dimensional Cavities for Single Cell Studies. Nano Letters (2014) 14: 4197–4204. $Co-corresponding authors (Impact Factor: 13; Top 4 Nanoscience & Nanotechnology Journal by Impact Factor); featured as front cover image (Cover Art).
Koch B, Sanchez S$, Schmidt CK$, Swiersy A, Jackson SP, Schmidt OG. Confinement and Deformation of Single Cells and Their Nuclei Inside Size-Adapted Microtubes. Adv Healthc Mater (2014) 3: 1753–1758. $Co-corresponding authors; featured as back cover image.
Roukos V, Voss TC, Schmidt CK, Lee S, Wangsa D, Misteli T. Spatial dynamics of chromosome translocations in living cells. Science (2013) 341: 660–664.
Schmidt CK and Jackson SP. On your MARK, get SET(D2), go! H3K36me3 primes DNA mismatch repair. Cell (2013) 153: 513-515.
Smith EJ, Xi W, Makarov D, Monch I, Harazim S, Quinones VAB, Schmidt CK, Mei YF, Sanchez S, Schmidt OG. Lab-in-a-tube: ultracompact components for on-chip capture and detection of individual micro-/nanoorganisms. Lab Chip (2012) 12: 1917-1931.
Harazim SM, Xi W, Schmidt CK, Sanchez S, Schmidt OG. Fabrication and applications of large arrays of multifunctional rolled-up SiO/SiO2 microtubes. J Mater Chem (2012) 22: 2878-2884.
Schneede A, Schmidt CK, Holtta-Vuori M, Heeren J, Willenborg M, Blanz J, Domanskyy M, Breiden B, Brodesser S, Landgrebe J et al. Role for LAMP-2 in endosomal cholesterol transport. J Cell Mol Med (2011) 15: 280-295.
Roukos V, Misteli T, Schmidt CK. Descriptive no more: the dawn of high-throughput microscopy. Trends in Cell Biology (2010) 20: 503-506.
Schulze S, Huang GS, Krause M, Aubyn D, Quinones VAB, Schmidt CK$, Mei YF$, Schmidt OG. Morphological Differentiation of Neurons on Microtopographic Substrates Fabricated by Rolled-Up Nanotechnology. Adv Eng Mater (2010) 12: B558-B564. $Co-corresponding authors
Schmidt CK, Brookes N, Uhlmann F. Conserved features of cohesin binding along fission yeast chromosomes. Genome Biol (2009) 10: R52.
Bernard P$, Schmidt CK$, Vaur S$, Dheur S, Drogat J, Genier S, Ekwall K, Uhlmann F, Javerzat JP. Cell-cycle regulation of cohesin stability along fission yeast chromosomes. Embo J (2008) 27: 111-121 $Co-first authors
D'Ambrosio C, Schmidt CK, Katou Y, Kelly G, Itoh T, Shirahige K, Uhlmann F. Identification of cis-acting sites for condensin loading onto budding yeast chromosomes. Genes Dev (2008) 22: 2215-2227.
Willenborg M, Schmidt CK, Braun P, Landgrebe J, von Figura K, Saftig P, Eskelinen, E-L. Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation. J Lipid Res (2005) 46: 2559–2569.
Eskelinen E$, Schmidt CK$, Neu S, Willenborg M, Fuertes G, Salvador N, Tanaka Y, Lüllmann-Rauch R, Hartmann D, Heeren J et al. Disturbed cholesterol traffic but normal proteolytic function in LAMP-1/LAMP-2 double-deficient fibroblasts. Mol Biol Cell (2004) 15: 3132–3145. $Co-first authors