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DNA repair & recombination

Our vision it to translate basic knowledge of DNA repair pathways into treatments for bone marrow failure syndromes and cancer.

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.

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.    

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.

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