DNA is the ideal biological molecule for encoding genomes due to its inherent stability. DNA damage repair (DDR) processes further promote genome stability during replication or upon exposure to endogenous or environmental DNA damaging agents. As such, DDR is involved in the aetiology of many human diseases. DDR suppresses cancer formation, by preventing mutation formation. DDR is a therapy target in cancer treatment – through radiation or chemotherapies, or more targeted precision therapies. Finally, DDR is emerging as an important tool in treatments of inherited disorders through gene editing.
Our team focuses on four lines of research that all aim to improve treatments for diseases involving DNA damage repair (DDR):
(1) identifying potential DDR targets for treating common cancers;
(2) defining DDR deficiencies that cause bone marrow failure and other childhood disorders;
(3) knowing how our cells regulate and activate DDR to prevent ageing and cancer; and
(4) creating new life-long treatments for genetic diseases using DDR gene editing therapies.
Current research projects
Pioneering application of gene editing to transplant using RNA (PAGETURNA)
Several rare childhood diseases cause shortened life because of loss of vital blood production. Collectively called bone marrow failure syndromes, they show great potential for treatment with gene editing. Our research focus is to use mRNA methods to deliver gene editing to bone marrow haematopoietic stem cells (HSCs) to treat these patients. In particular, we have pioneered a technique called Prime Editing – which we can show has exquisite ability to correct genetic mutations in HSCs. In addition to getting Prime Editing to work in this difficult cell type, we have also improved the range of targets that can be edited using novel Prime Editors combinations. Finally, by manipulating DNA damage repair (DDR) in target cells, we can increase the efficiency of on-target editing, and reduce the number of deletions and insertions that cause editing to fail.
Our short-term goal is to show in model systems that gene edited cells produce normal blood. Our medium-term goal is to use editing in HSCs of bone marrow failure syndrome patients, as a one-off, life-long curative therapy.The role of BLM, a gene mutated in Bloom Syndrome
Bloom Syndrome is a rare inherited disorder that results in greater than 90% risk of developing cancer by the age of 25. The gene that causes Bloom Syndrome, called BLM, protects cells from cancer-causing mutations, hence affected individuals develop the same types of cancers as the general population, only much faster. We investigate the properties of the BLM gene product to understand how it protects us from cancer and may influence some forms of cancer treatment.Novel inhibitors of DNA repair as chemotherapy sensitisers in breast cancer
Using our knowledge of how DNA repair proteins interact, we have designed new inhibitors that can sensitise cancer cells to chemotherapy. We are working to improve these inhibitors so that they may one day be useful in cancer treatment.The role of FANCM, a gene mutated in Fanconi anaemia
Fanconi anaemia is an inherited disorder with greatly elevated risk of leukaemia and cancers. A causal gene called FANCM is a ‘tumour suppressor’. Our work is uncovering its tumour suppressor function: a complex function in repair of damage to our DNA. This study aims to understand how this protects us from cancer and may influence some forms of cancer treatment.
- Sylvie van Twest, Research Assistant
- Vince Murphy, Research Assistant
- Lara Abbouche, PhD student
- Lorna McLeman, PhD student
- Shraddha Kameshwar, PhD student
- Lu Liu, PhD student
- Leehy Rosinger, Masters Student
Hodson, C, Low, JKK, van Twest, S, Jones, SE, Swuec, P, Murphy, V, Tsukada, K, Fawkes, M, Bythell-Douglas, R, Davies, A, Holien, JK, O’Rourke, JJ, Parker, BL, Glaser, A, Parker, MW, Mackay, JP, Blackford, AN, Costa, A, and DEANS, AJ (2022) ‘Mechanism of Bloom syndrome complex assembly required for double Holliday junction dissolution and genome stability’ PNAS, 119, e2109093119 10.1073/pnas.2109093119
Sharp MF, Bythell-Douglas R, Deans AJ and Crismani W, The Fanconi Anaemia ubiquitin E3 ligase complex as an anti-cancer target 2021 Molecular Cell. 10.1016/j.molcel.2021.04.023
Jung, Moonjung; Ramanagoudr-Bhojappa, Ramanagouda; van Twest, Sylvie; Rosti, Rasim Ozgur; Murphy, Vincent; Tan, Winnie; Donovan, Frank X; Lach, Francis P; Kimble, Danielle C; Jiang, Caroline S; Roger Vaughan, Parinda A Mehta, Filomena Pierri, Carlo Dufour, Arleen D Auerbach, Deans, AJ*, Agata Smogorzewska*, Settara C Chandrasekharappa* (co-corresponding). Association of clinical severity with FANCB variant type in Fanconi anemia 2020. Blood 10.1182/blood.2019003249
Tan, Winnie; van Twest, Sylvie; Leis, Andrew; Bythell-Douglas, Rohan; Murphy, Vincent J; Sharp, Michael; Parker, Michael W; Crismani, Wayne; DEANS, Andrew J; Monoubiquitination by the human Fanconi Anemia core complex clamps FANCI: FANCD2 on DNA in filamentous arrays, 2020 eLife. 10.7554/eLife.54128
Lu, R, O’rourke, J, Sobinoff AP, Allen J, Nelson CB, Tomlinson,CG, Deans, AJ* and Pickett, HA* (*co-corresponding authors) The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT) 2019. Nature Communications, 10(1):2252 10.1038/s41467-019-10180-6
Van Twest S, Murphy VJ, Hodson C, Tan W, Swuec P, O’Rourke, JJ, Heierhorst, J, Crismani, W and Deans AJ 2017. Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway. Molecular Cell. 65(2):247–59. 10.1016/j.molcel.2016.11.005
ORCID profile: https://orcid.org/0000-0002-5271-4422
Google Scholar profile: https://scholar.google.com.au/citations?user=45jy-QUAAAAJ&hl=en