Madalena Tarsounas Ph.D.

Telomeres and Genome Stability Group
How homologous recombination (HR), the major error-free pathway for DNA repair in mammalian cells, regulates telomeres and acts to prevent genomic instability, the underlying mechanism of many cancers.

Dr Madalena Tarsounas

Email 
Tel  +44 (0)1865 617319
Contact address  Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ
Department  Department of Oncology
College No College

Research Summary

Genome instability is a hallmark of human tumours. DNA mutations and genome rearrangements are in almost all cases responsible for the aberrant proliferation and metastatic behaviour of cancer cells. Work in Dr. Madalena Tarsounas’ laboratory aims to understand the causes of genome instability and the cellular mechanisms responding to it. This will not only enhance possibilities of cancer prevention, but also the development of treatment modalities that exploit the DNA damage tolerance of cancer cells.

Telomeres are structures at chromosome ends, consisting of repetitive DNA sequences and associated proteins. They protect chromosome ends from degradation and fusion, both of which cause genome instability similar to unrepaired DNA double-strand breaks. Telomere dysfunction is often associated with the onset of tumorigenesis. The work in Dr. Tarsounas laboratory investigates how factors involved in DNA repair by homologous recombination contribute to the establishment of protective telomeric structures and how they facilitate the successful completion of telomere replication. An important aspect of this work is understanding the DNA damage response emanating from unprotected or damaged telomeres. These studies are extended to analyse how components of the shelterin telomeric complex contribute to telomere protection and tumour suppression.

Another major line of investigation in Dr. Tarsounas laboratory is the action of homologous recombination proteins at sites of ionizing radiation-induced DNA damage. A group of five essential homologous recombination factors, the RAD51 paralogs, is currently under investigation. These form complexes with each other to promote DNA double strand break repair, however their mechanism of action is still poorly understood. Previous work in the Tarsounas laboratory has shown that a key role of at least two of the RAD51 paralogs, RAD51C and XRCC3, is to mediate the generation of a DNA damage signal at break sites, required for the appropriate cellular response to damage. The study of the role of RAD51C/XRCC3 at break sites will help our understanding how DNA damage sites are efficiently recognised, possibly by remodelling the chromatin landscape surrounding DNA breaks. This work will also investigate how the other RAD51 paralog family members function at DNA breaks, both in the early steps of initiating homologous recombination reactions, as well as during subsequent steps that complete the repair process.

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Sources of Funding

  • Cancer Research UK
  • The Royal Society
  • EMBO Young Investigator

Collaborators

Group Members

  • Dr Cecilia Folio Zabala, Postdoctoral Researcher
  • Dr Hilda Mujcic, Postdoctoral Researcher
  • Dr Xianning Lai, Postdoctoral Researcher
  • Sophie Badie, Scientific Officer
  • Eliana Tacconi, CR-UK DPhil student
  • Jutta Zimmer, MRes Student

Collaborators

    Biography

    Dr Madalena Tarsounas is a Cancer Research UK Senior Group Leader within the CRUK/MRC Oxford Institute for Radiation Oncology within the Department of Oncology at the University of Oxford and leads the Telomeres and Genome Stability group. Her research focuses on gaining a greater understanding of how homologous recombination, the major error-free pathway for DNA repair in mammalian cells, regulates telomeres and acts to prevent genomic instability, the underlying mechanism of many cancers.

    Dr Tarsounas came to Oxford in 2005 as a Junior Group Leader within the Gray Institute for Radiation Oncology and Biology. After obtaining her PhD at York University in Toronto, Canada, she undertook post-doctoral training with Cancer Research UK at the Clare Hall Laboratories within the London Research Institute, during which she held post-doctoral fellowships from the European Molecular Biology Organization (EMBO) and The Breast Cancer Campaign. In 2011, she received an EMBO Young Investigator Award.

    Dr. Tarsounas has authored or co-authored over 30 publications and been invited to present her work at national and international conferences. She was also co-organizer of international meetings, including the EMBO Workshop on “Chromosome structure, damage and repair” and the Ramon Areces Symposium on “Telomeres and telomerase” in 2011.

    Nov 2011 Senior Group Leader, the CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford

    Dec. 2005 Group Leader, The CRUK/MRC Gray Institute for Radiation, Oncology and Biology, University of Oxford

    1999-2005 Postdoctoral FellowCancer Research UK , Clare Hall Laboratories

    Awards Training and Qualifications

    • 2010, EMBO Young Investigator Award,
    • 2010, University Research Lecturership, University of Oxford
    • 2003, Post Doctoral Fellowship, Breast Cancer Campaign
    • 2001, Post Doctoral Fellowship, Cancer Research UK
    • 1999, Post Doctoral Fellowship, European Molecular Biology Organization (EMBO)
    • 1999, Ph.D., York University, Toronto, Canada
    • 1995, M.Sc., York University, Toronto, Canada

    Publications

    Selected Publications:

    Tarsounas M, Tijsterman M. (2013) 'Genomes and G-quadruplexes: for better or for worse.' J Mol Biol.  Nov 29;425(23):4782-9.

    Carlos AR, Escandell JM, Kotsantis P, Suwaki N, Bouwman P, Badie S, Folio C, Benitez J, Gomez-Lopez G, Pisano D, Jonkers J, and Tarsounas M (2013). ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets. Nat Commun, 4:2697.

    Tarsounas M (2013). It's getting HOT at telomeres. EMBO J, 32(12):1655-7.

    Thanasoula M, Escandell J, and Tarsounas M (2012). ATM/ATR checkpoint activation downregulates CDC25C to prevent mitotic entry with uncapped telomeres. EMBO J , 31:3398-3410.

    Tejera* A, Stagno d´Alcontres* M, Thanasoula M, Martinez P, Liao C, Tarsounas M, and Blasco M (2010). TPP1 is required for TERT recruitment, telomere elongation and normal skin development in mice. Developmental Cell, 18(5):775-789.

    Thanasoula M, Escandell J, Martinez P, Badie S, Munoz P, Blasco M, and Tarsounas M (2010).
    p53 Prevents entry into mitosis with uncapped telomeres. Curr Biol, 20(6):521-6.

    Martinez P, Thanasoula M, Carlos A, Gomez G, Tejera A, Schoeftner S, Dominguez O, Pisano D, Tarsounas M, and Blasco M (2010). Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nat Cell Biol, 12(8):768-780.

    Bouwman* P, Aly* A, Escandell* J, Pieterse M, Bartkova J, van de, Hiddingh S, Thanasoula M, Kulkarni A, Yang Q, Haffty B, Tommiska J, Blomqvist C, Drapkin R, Adams D, Nevanlinna H, Bartek J, Tarsounas* M, Ganesan* S, and Jonkers* J (2010). 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers (*equal contribution and equal corresponding author). Nat Struct Mol Biol, 17(6):688-695.

    Badie S, Escandell  J, Bouwman  P, Carlos  A, Thanasoula  M, Gallardo  M, Suram  A, Jaco  I, Benitez  J, Herbig  U, Blasco  M, Jonkers  J, and Tarsounas  M (2010). BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping. Nat Struct Mol Biol. , 17:1461-69.

    Martinez P, Thanasoula M, Munoz P, Liao C, Tejera A, McNees C, Flores J, Fernandez-Capetillo O, Tarsounas M, and Blasco M (2009). Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice.
    Genes Dev, 23(17):2060-75.

    Badie S, Liao C, Thanasoula M, Barber P, Hill M, and Tarsounas M (2009). RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation. J Cell Biol, 185(4):587-600.

    Siderakis M, and Tarsounas M (2007). Telomere regulation and function during meiosis.
    Chromosome Res, 15(5):667-79.

    *Liu Y, *Tarsounas M, O'regan P, and West S (2007). Role of RAD51C and XRCC3 in genetic recombination and DNA repair. J Biol Chem, 282(3):1973-9.

    Tarsounas M, and West S (2005). Recombination at mammalian telomeres: an alternative mechanism for telomere protection and elongation. Cell Cycle, 4(5):672-4.

    Tarsounas M, Munoz P, Claas A, Smiraldo P, Pittman D, Blasco M, and West S (2004).
    Telomere maintenance requires the RAD51D recombination/repair protein. Cell, 117(3):337-47.

    Tarsounas M, Davies A, and West S (2004). RAD51 localization and activation following DNA damage. Philos Trans R Soc Lond B Biol Sci, 359(1441):87-93.

    Tarsounas M, Davies D, and West S (2003). BRCA2-dependent and independent formation of RAD51 nuclear foci. Oncogene, 22(8):1115-23.

    Madsen B, Tarsounas M, Burchell J, Hall D, Poulsom R, and Taylor-Papadimitriou J (2003).
    PLU-1, a transcriptional repressor and putative testis-cancer antigen, has a specific expression and localisation pattern during meiosis. Chromosoma, 112(3):124-32.

    Moens P, Kolas N, Tarsounas M, Marcon E, Cohen P, and Spyropoulos B (2002). The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination. J Cell Sci, 115(Pt 8):1611-22.

    Tarsounas M, Pearlman R, and Moens P (2001). CLIP-50 immunolocalization during mouse spermiogenesis suggests a role in shaping the sperm nucleus. Dev Biol, 236(2):400-10.

    Tarsounas M, and Moens P (2001). Checkpoint and DNA-repair proteins are associated with the cores of mammalian meiotic chromosomes. Curr Top Dev Biol, 51:109-34.

    Masson J, Tarsounas M, Stasiak A, Stasiak A, Shah R, McIlwraith M, Benson F, and West S (2001). Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev, 15(24):3296-307.

    Constantinou A, Tarsounas M, Karow J, Brosh R, Bohr V, Hickson I, and West S (2000).
    Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. EMBO Rep, 1(1):80-4.

    Moens P, Freire R, Tarsounas M, Spyropoulos B, and Jackson S (2000). Expression and nuclear localization of BLM, a chromosome stability protein mutated in Bloom's syndrome, suggest a role in recombination during meiotic prophase. J Cell Sci, 113 ( Pt 4):663-72.

    Tarsounas M, Morita T, Pearlman R, and Moens P (1999). RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and synaptonemal complexes.
    J Cell Biol, 147(2):207-20.