TARSOUNAS GROUP
Genome Stability and Tumourigenesis
RESEARCH SUMMARY
BRCA1 and BRCA2 genes are mutated in about a quarter of familial breast and ovarian cancers. However, familial cancers represent only a small fraction of all cancers (Figure 1). In recent years, whole genome sequencing of large number of human tumours revealed that a significant fraction of non-familial breast and ovarian cancers carry BRCA1and BRCA2 mutations and that these mutations are also found in other types of sporadic cancer (Figure 2). Importantly, triple negative breast cancers, associated with one of the most aggressive forms of the disease, are significantly enriched in BRCA1 and BRCA2 mutations.


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. One entry point into understanding this paradox is the key role of BRCA1 and BRCA2 proteins in facilitating accurate DNA replication by helping stalled forks to re-start (Figure 3). Consequently, cells with compromised BRCA1/2 function accumulate stalled replication forks, which, in turn, leads to replication-associated DNA damage. These pathological DNA lesions are lethal to normal cells, where DNA damage checkpoints and responses are functional. However, cancer cells lack DNA damage responses; they can proliferate and become tumourigenic in spite of DNA damage accumulation.

Work conducted in my laboratory aims to unravel the mechanisms underlying replication failure in BRCA1/2-deficient cells and how this knowledge can be exploited for the development of novel treatments that could selectively kill tumour cells with compromised BRCA1/2 function. To achieve these goals, my laboratory is using experimental approaches that combine tissue culture, molecular biology and microscopy, with high-throughput technologies and bioinformatics (Figure 4).

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Madalena Tarsounas
Professor of Molecular & Cell Biology
madalena.tarsounas@oncology.ox.ac.uk
+44 (0)1865 617319
RESEARCH THEMES
GROUP MEMBERS
Rebecca Dagg - CRUK Postdoctoral Researcher
SELECTED PUBLICATIONS
- Tarsounas, M. and Sung, P., (2020) The antitumorigenic roles of BRCA1-BARD1 in DNA repair and replication, Nature Reviews Molecular Cell Biology, 21, pp. 284–299
- Reisländer, T. et al, (2019) BRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors, Nature communications, 10, Article number: 3143
- Tacconi, E.M. et al (2019) Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance, EMBO Molecular Medicine, 11
- Tacconi E.M. et al (2017) BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity, EMBO Molecular Medicine, 9, pp. 1398-1414
- Lai, X. et al (2017) MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells, Nature Communications, 8, Article number: 15983
- Michl, J. et al (2016) FANCD2 limits replication stress and genome instability in cells lacking BRCA2, Nature Structural & Molecular Biology, 23, pp. 755-757
- Michl, J. et al (2016) Interplay between Fanconi anemia and homologous recombination pathways in genome integrity, The EMBO Journal, 35, pp. 909-923
- Zimmer, J. et al (2016) Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds, Molecular Cell, 61, 449 - 460
- Chaikuad, A. et al (2014) A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics, Nature Chemical Biology, 10, pp. 853-860
- Bouwman, P. et al (2010) 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers, Nature Structural & Molecular Biology, 17, pp. 688-695
- Badie, S. et al (2015) BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres, The EMBO Journal, 34, p. 828