Genome stability

The Genome Stability Unit focuses on the mechanisms cells use to protect themselves from cancer-causing mutations.

Research Overview

We study familial cancer syndromes that cause predisposition to breast/ovarian cancer, leukaemias and other solid tumours. These families inherit a defect in the ability to maintain genome stability – their cells accumulate mutations at a faster rate, and thus cancer occurs earlier in life with a higher probability. This mechanism of genome stability is intricate and involves a number of signaling and DNA repair pathways. We are beginning to reconstitute these pathways biochemically using recombinant proteins and synthetic DNA molecules to understand how they function and how they could be targeted with new types of cancer drugs. We also study the chemotherapeutic sensitivity of human tumour cell lines that have defects in maintaining genome stability.

Read Andrew’s article that appeared in the Melbourne Review, for an in-depth discussion about the way maintaining genome stability protects against breast cancer.

Research Themes

New breast cancer predisposition genes

In about 50% of families with a strong family history of breast cancer, the responsible gene is not known. New technology that allows sequencing of the entire DNA of such families has linked defects in genome stability genes with cancer predisposition. We are investigating whether the identified defects (1) inhibit the normal function in maintaining genome stability; (2) are affected during the development of breast cancer and (3) make the resultant cancer more treatable with certain types of chemotherapy.

The role of BLM, a gene mutated in Bloom’s Syndrome

Bloom’s 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’s 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 and 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 about 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 treatment of cancer.

The role of FANCM, a gene mutated in Fanconi anemia

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.

Student Projects


Publication Highlights

  1. Swuec P, Renault L, Borg A, Shah H, Murphy VJ, van Twest S, Snijders A, Deans AJ, Costa A The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2. Cell Reports 2017 18:3; 611-623
  2. van Twest S, Murphy VJ, Hodson C, Tan W, Swuec L, O'Rourke JJ, Heierhorst J, Crismani W, Deans AJ Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway. Molecular Cell 2017 65:2; 247-259
  3. Coulthard, R*, Deans, AJ*, Swuec, P, Bowles, M, Costa, A, West, SC, and McDonald, NQ ‘Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex’ Structure 2013 21, 1648-58
  4. Walden, H and Deans, AJ. ‘The Fanconi Anemia DNA Repair Pathway: Structural and Functional Insights into a Complex Disorder’ Annual Review of Biophysics, 2014, 43:in press.
  5. Deans, AJ. ‘Fanconi proteins get histones moving’ EMBO J 2012 31 (17), 3511-3512
  6. 'The DNA translocase activity of FANCM protects stalled replication forks’ AN Blackford, RA Schwab, J Nieminuszczy, AJ Deans, SC West, ...Human molecular genetics 2013 21:2005-2016
  7. Deans, AJ and West, SC. DNA interstrand crosslink repair and cancer. Nature Reviews Cancer 2011 11:467-480
  8. MacKay C, Déclais, AC, Lundin C, Agostinho A, Deans, AJ, MacArtney, TJ, Hofmann, K, Gartner, A, West, SC, Helleday, T, Lilley DMJ and Rouse, J. Identification of KIAA1018/FAN1, a DNA Repair Nuclease Recruited to DNA Damage by Monoubiquitinated FANCD2. Cell 2010 142:65-76
  9. Deans, AJ and West, SC. FANCM connects the genome instability disorders Bloom’s Syndrome and Fanconi Anemia. Molecular Cell 2009 36, 943-953
  10. Spurdle AB, Deans AJ, Duffy D, Goldgar DE, Chen X, Beesley J; kConFaB, Easton DF, Antoniou AC, Peock, S, Cook M; EMBRACE Study Collaborators, Nathanson KL, Domchek SM, Macarthur GA, Chenevix-Trench G. No evidence that CDKN1B (p27) polymorphisms modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2009 115:307-13