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DNA repair & recombination

Our vision is to translate basic knowledge of DNA repair pathways to treatments for cancer, bone marrow failure syndromes, and infertility.

We are interested in understanding the fundamentals of DNA repair pathways in both somatic and reproductive cells. In particular, we focus on the Fanconi anaemia pathway, which is essential for repair of crosslinked DNA. We are using the advances that we and other groups are making to identify and characterise potential new treatments for diseases that are caused by problems of DNA repair.

We also focus on how pathways that maintain genome stability in somatic cells also regulate repair of double-strand breaks at meiosis. The orchestrated formation and repair of these breaks are used to generate genetic diversity and keep chromosome numbers constant from one generation to the next.

We collaborate closely with all members of the Genome Stability Unit at SVI.

Members of our laboratory have established a support group with families affected by Fanconi anaemia. The organisation, FASA, is membership-driven and aims to unite and inform the FA community in Australia, New Zealand and beyond.

Research Themes

Development of targeted therapeutics for cancer and rare disease

When one genetic pathway is mutated (e.g. BRCA1/2), there can be an increased reliance on another second genetic pathway (e.g. PARP). This second pathway can be targeted in the case of certain cancers and exploits a weakness of the cancer. This relationship is known as synthetic lethality. We are discovering new synthetic lethal relationships in the DNA damage response and are developing the therapeutic tools to exploit them.

The role of FANCM in mammalian reproduction

FANCM is a protein that can remodel a range of unique DNA structures, particularly structures that occur during DNA replication and repair. Similarly, FANCM is important to keep a number of serious diseases at bay. One of our many interests with this protein is how and why it is required for normal fertility and meiosis.    

Understanding the molecular mechanisms of cancer predisposition and reducing the burden of common cancers in Australia

For people with Fanconi anaemia (FA), mouth cancer remains a serious problem. People with FA get mouth cancer at much younger ages than in the general population and often without any known cause. When discovered early, mouth cancer can be treated relatively easily, but treatment becomes much more difficult when cancer is found at later stages. New methods are being developed to detect very early signs of mouth cancer in simple, noninvasive ways. One of these methods involves brushing samples from the mouth with soft brushes and testing these samples for abnormal cells. 
We are currently conducting a research study to see if this test would be helpful for people with FA. We are also interested in learning more about molecules in the saliva that could indicate the presence of cancer and improving research collaborations in FA. We are recruiting people with FA to help us with this research study through participating in one or more of the following: donating a small blood sample, brushing certain places in the mouth with soft brushes under our guidance, completing a health questionnaire, and keeping in touch with us.
We would greatly appreciate your help with this project. If you think you might be interested in joining or want to learn more, please contact Dr Wayne Crismani [email protected]

Student Projects

Staff

Publication Highlights

  1. Crismani, W., Girard, C., Froger, N., Pradillo, M., Santos, J. L., Chelysheva, L., Copenhaver, G. P., Horlow, C., Mercier, R. (2012). FANCM limits meiotic crossovers. Science, 336(6088) 1588-1590 DOI: 10.1126/science.1220381. Recommended by F1000.
  2. Crismani, W.†, Portemer, V.†, Froger, N., Chelysheva, L., Horlow, C., Vrielynck, N., Mercier, R. (2013). MCM8 is required for a pathway of meiotic double-strand break repair independent of DMC1 in Arabidopsis thaliana. PLoS Genetics, 9(1), e1003165.
  3. Crismani, W.†, Girard, C.†, Froger, N., Mazel, J., Lemhemdi, A., Tran, J., Horlow, C., Mercier, R. (2014) FANCM-associated proteins MHF1 and MHF2, but not the other Fanconi factors, limit meiotic crossovers. Nucleic Acids Research, 42(14), 9087-95.
  4. Crismani, W.†, Séguéla-Arnaud, M.†, Mazel, J., Froger, N., Choinard, S., Lemhemdi, A., N. Macaisne, N.,  Van Leene, J., Gevaert, K., De Jaeger, G., Chelysheva, L., Mercier, R. (2015) Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM. PNAS, 112(15), 4713-18.
  5. Girard, C., Chelysheva, L., Choinard, S., Froger, N., Macaisne, N., Lemhemdi, A., Mazel, J., Crismani, W.†, Mercier, R.† (2015) AAA-ATPase FIDGETIN-LIKE 1 and helicase FANCM antagonize meiotic crossovers by distinct mechanisms. PLoS Genetics, 11(9): e1005448. Corresponding author†.
  6. Cifuentes, M., Jolivet, S., Cromer, L., Harashima, H., Bulankova, P., Renne, C., Crismani, W., Nomura, Y., Nakagami, H., Sugimoto, K., Schnittger, A., Riha, K., Mercier, R. (2016) TDM1 regulation determines the number of meiotic divisions PLoS Genetics, 12(2):e1005856.
  7. Séguéla-Arnaud, M., Choinard, S., Larchevêque, C., Girard, C., Froger, N., Crismani, W., Mercier, R. (2016)  RMI1 and TOP3a limit meiotic CO formation through their C-terminal Domains. Nucleic Acids Research.
  8. Van Twest S, Murphy VJ, Hodson C, Tan W, Swuec P, O’Rourke JJ, Heierhorst, J., Crismani, W., Deans, A. (2016) Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway. Molecular Cell
  9. Tsui, V. & Crismani, W. (2019) The Fanconi Anemia pathway and fertility. Trends in Genetics.
  10. Kolinjivadi, A.M., Crismani, W., and Ngeow, J. (2020). Emerging functions of Fanconi Anemia genes in replication fork protection pathways. Hum. Mol. Genet.
  11. Tan, W., van Twest, S., Leis, A., Bythell-Douglas, R., Murphy, V.J., Sharp, M., Parker, M.W., Crismani, W., and Deans, A.J. (2020a). Monoubiquitination by the human Fanconi Anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays. Elife 9.
  12. Tan, W., Murphy, V.J., Charron, A., van Twest, S., Sharp, M., Constantinou, A., Parker, M.W., Crismani, W., Bythell-Douglas, R., and Deans, A.J. (2020b). Preparation and purification of mono-ubiquitinated proteins using Avi-tagged ubiquitin. PLoS One 15, e0229000.
  13. Sharp, M.F., Murphy, V.J., Twest, S. Van, Tan, W., Lui, J., Simpson, K.J., Deans, A.J., and Crismani, W. (2020). Methodology for the identification of small molecule inhibitors of the Fanconi Anaemia ubiquitin E3 ligase complex. Sci. Rep. 10, 7959.
  14. Crismani, W., and Mercier, R. (2020). Don’t Forget Your Sister: Directing Double-Strand Break Repair at Meiosis. Dev. Cell 53, 374–376.

PATENTS
1. Day, K., May, G., Crismani, W., Shares, J. A., Yun, Y. (2016) US Patent Application 15/211053, filed July 15th 2016. Obtaining the genotype of a male gametic cell.
2. Mercier, R., Crismani, W., Girard, C. (2015), Increase in meiotic recombination in plants by inhibiting the FIDG protein. WO patent application 2015001467 A1 – licensed
3. Mercier, R., Crismani, W., Séguela-Arnaud, M. (2015), Increase in meiotic recombination in plants by inhibiting either RECQ4 or TOP3A of the RTR complex. WO patent application 2015181647 A1 – licensed
4. Mercier, R. & Crismani, W. (2013), Increase in meiotic recombination in plants by inhibiting the FANCM protein. WO patent application 2013038376 A1 – licensed