Our research is focused on gaining a greater understanding of how homologous recombination (HR), the major DNA repair pathway in mammalian cells, helps to prevent genomic instability, the underlying mechanism of many cancers. In particular, we study how tumor cells lacking BRCA1 or BRCA2 gene function differ from normal cells in their responses to exogenous damage induced by ionizing radiation, as well as to cell-intrinsic challenges that arise during DNA replication.
A conundrum regarding the breast cancer-promoting BRCA1 and BRCA2 gene mutations is that their introduction into normal cells causes cell cycle arrest and embryonic lethality, and not the rampant cell proliferation characteristic of tumours bearing the same mutations.
Following up on our finding that 53BP1 inactivation reverses the cell cycle arrest induced by BRCA1, but not BRCA2 inactivation (Bouwman et al., Nat. Struct. Mol. Biol. 2010), we searched for mutations that can circumvent the proliferative arrest in cells carrying BRCA2 gene deletion. We thus identified ARF as a barrier to uncontrolled proliferation and tumorigenesis onset upon loss of BRCA2 function (Carlos, Escandell et al., Nat. Commun. 2013).
Conversely, using a genetic screen for synthetic lethal interactions with BRCA2 deletion, we discovered that ERK1 (as well as other enzymes of the MAPK pathway) is required to sustain viability of Brca2-deleted cells, regardless of their p53 status (Carlos, Escandell et al., Nat. Commun. 2013). Following up on this, we characterized a novel, highly-selective and potent inhibitor of ERK1/2 kinases released by Merck and demonstrated its in vivo prolonged on-target activity and exceptional specificity in killing BRCA2-deficient cells (Chaikuad et al., Nat. Chem. Biol. 2014).
We have demonstrated that the tumour suppressors BRCA1 and BRCA2 are required for the replication of genomic regions with G quadruplex-forming potential, including telomeres, where they can suppress the genomic instability stemming from inefficient replication of these sites. Indeed, drugs that stabilise G quadruplex structures are particularly toxic to BRCA1/2-deficient cells, highlighting their therapeutic potential in targeting BRCA-deficiency (Zimmer et al., Mol. Cell 2016).
More recently, my group identified a novel synthetically lethal interaction between BRCA2 and FANCD2 gene deletions. Mechanistically, FANCD2 acts to limit constitutive replication stress in BRCA2-deficient cells, which impacts on cell survival and the response to olaparib treatment (Michl, Zimmer et al., Nat. Struct. Mol. Biol 2016).
My laboratory has developed systematic and comprehensive approaches that enabled identification of compounds with specific activity against BRCA1/2-deficient cells, including those that have acquired chemotherapy resistance. Our current work is focused on understanding the mechanism of action of these compounds at cellular level, as well as on their initial validation in pre-clinical settings (xenograft models). We are assessing the efficacy of these drugs in models for chemotherapy resistance or as enhancers of the radiation sensitivity intrinsic to BRCA1/2-deficient cells/tumours.
This body of work is deeply relevant to the search for treatments that would selectively kill tumour cells whose capacity for homologous recombination-mediated repair has been compromised and it has, in the longer term, a realistic chance of helping cancer prevention and treatment.
Madalena Tarsounas is Professor of Molecular and Cell Biology (since 2015) and a CRUK Group Leader within the CRUK/MRC Oxford Institute for Radiation Oncology (since 2006). After obtaining her PhD at York University in Toronto, Canada (1999), she undertook postdoctoral training at the CRUK Clare Hall Laboratories of the London Research Institute (1999-2005), where she held postdoctoral fellowships from the European Molecular Biology Organization (EMBO) and the Breast Cancer Campaign. In 2010, she was elected EMBO Young Investigator. In 2011 Madalena has initiated the EMBO Conference Series on ‘DNA damage responses in cell physiology and disease’ held in Cape Sounio, Greece, which has since become a biennial international event.
Tacconi EM, Lai X, Folio C, Porru M, Zonderland G, Badie S, Michl J, Sechi I, Rogier M, Matía García V, Batra AS, Rueda OM, Bouwman P, Jonkers J, Ryan A, Reina-San-Martin B, Hui J, Tang N, Bruna A, Biroccio A, Tarsounas M. BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity EMBO Mol Med. 2017 Jul 20. pii: e201607446. doi: 10.15252/emmm.201607446. [Epub ahead of print]
Lai X, Broderick R, Bergoglio V, Zimmer J, Badie S, Niedzwiedz W, Hoffmann JS, Tarsounas M. MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells Nat Commun. 2017 Jul 17;8:15983. doi: 10.1038/ncomms15983
Michl J, Zimmer J, Buffa FM, McDermott U, Tarsounas M.FANCD2 limits replication stress and genome instability in cells lacking BRCA2. Nat Struct Mol Biol. 2016 Jun 20. doi: 10.1038/nsmb.3252.
Michl J, Zimmer J, Tarsounas M. Interplay between Fanconi anemia and homologous recombination pathways in genome integrity. EMBO J. 2016 May 2;35(9):909-23.
Zimmer J, Tacconi EM, Folio C, Badie S, Porru M, Klare K, Tumiati M, Markkanen E, Halder S, Ryan A, Jackson SP, Ramadan K, Kuznetsov SG, Biroccio A, Sale JE, Tarsounas M.Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds. Mol Cell. 2016 Feb 4;61(3):449-60.
Badie S*, Carlos AR*, Folio C*, Okamoto K, Bouwman P, Jonkers J and Tarsounas M. 2015 BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres. EMBO J. 34:410-424. *equal first-author contribution.
Tacconi E and Tarsounas M. 2014. How homologous recombination maintains telomere integrity. Review. Chromosoma 124: 119-130.
Sjögren C, Tarsounas M, Bartek J, Hoog C. 2014. Introduction (Editorial). Exp Cell Res 14, 434.
Chaikuad A, Tacconi E, Zimmer J, Liang Y, Gray NS, Tarsounas M* and Knapp S*. 2014. A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. Nat. Chem. Biol. 10:853-860. * equal corresponding authors.
Sophie Badie, Scientific Officer
Danielle Bianchi, MSc Student (visiting)
Rebecca Dagg, Postdoctoral Researcher
Giuliana de Grigoriis, Postdoctoral Researcher
Carlotta Mazzitelli, Research Assistant
Timo Reislander, DPhil student
Gijs Zonderland, MSc student