Genome Surveillance and Stability

  • Our group is generally interested in the regulation of the DNA Damage Response (DDR), and in particular in its regulation during the early steps of embryonic development. The main function of the DDR is to slow down, or arrest cell prolferation in the presence of DNA lesions (DNA breaks, telomer integrity, replication forks stall) so to avoid cell division in the presence of DNA damage and therefore avoid the propagation of mutations that are drivers of genomic instability. A strong genomic instability is a feature of cancer cells (telomeric fusions, trabnsocations, duplications, deletions). To date it is admitted that the majority of sporadic tumours are the consequence of mutations in DDR genes, which can also lead to the development of genetic diseases. Hence the DDR is currently considered as a major barrier to malignat transformation playing a key role in maintenace of genomic stability.


    To date, our research is funded by:

    logo Ligue contre le cancer
    logo arc
    logo frm
    logo MSD avenir
    logo inserm

      Learn more

    Members

    Antoine Aze
    Aze Antoine
    Domenico Maiorano
    Maiorano Domenico
    Nathalie Malirat
    Malirat Nathalie
    Éric Morency
    Morency Éric
    Elena Lo Furno
    Lo Furno Elena

    Publications

    An ATR-dependent function for the Ddx19 RNA helicase in nuclear R-loop metabolism

    Hodroj D, Recolin B, Serhal K, Martinez S, Tsanov N, Abou Merhi R, Maiorano D

    2017 - EMBO J., 36(9):1182-1198

    Request for full article28314779

    Rad18 is a maternal limiting factor that suppresses the UV-dependent DNA damge checkpoint in Xenopus embryos

    Kermi, C., Prieto, S., van der Laan, S., Tsanov, N., Recolin, B., Uro-Coste, E., Delisle, M-B., and Maiorano, D.

    2015 - Developmental Cell , 34(3):364-372

    Request for full article26212134

    High Dub3 expression in mouse ESC couples the G1/S checkpoint to pluripotency

    Van der Laan, S., Crozet, C., Tsanov, N., and Maiorano, D

    2013 - Molecular Cell, 52, 3, 366-379

    Request for full article24207026

    DNA polymerase k-dependent DNA synthesis at stalled replication forks is important for Chk1 activation

    Bétous R., Pillaire, M-J, Pierini, L., Van der Laan, S., Recolin B., Ohl-Séguy, E., Guo, C., Niimi, N., Gruz, P., Nohmi, T. Friedberg, E., Cazaux, C., Maiorano, D* and Hoffmann J-S*. * corresponding authors

    2013 - EMBO Journal, 32(15):2172-85

    Request for full article23799366
    Display all the publications

    Publications of the team

  • DDR regulation during early embryogenesis

    It has been known for a longtime that the DDR is inefficient in the early embryos, however the reasons for this regulation and the underlying molecular bases are poorly understood. We have explored this issue in the early embryos of the clawed frog Xenopus laevis as well as in mouse embryonic stem cells (ES cells).
    In Xenopus, we have discovered that the DDR is inefficient because the embryos efficiently by-pass DNA lesions by constitutive activation of the DNA damage tolerance pathway involving translesion DNA synthesis. This regulation limits replication fork stalling in front of DNA lesions and therefore DDR activation (Figure 1). We are currently exploring the consequences of constitutive translesion synthesis activation on genomic stability during early embryogenesis.

    figure 2 fr
    Figure 1. Constitutive activation of translesion DNA synthesis inhibts DDR activation during early Xenopus development. (Adapted from Kermi et al., Dev Cell 2015).

    Mouse embryonic stem cells (ES) also display an inefficient DDR for the G1/S checkpoint and by consequence show several signs of genomic instability. We have discovered that in these cells the G1/S checkpoint is inefficient because the critical G1/S regulator, the CDC25A protein phosphatase, is very abundant. We have also identifed the molecular bases of this abundance by showing that its stability depends upon the Dub3 ubiquitine hydrolase whose expression is under control of two pluripotency factors, Esrrb and Sox2 (van der Laan et al., 2013 Mol Cell and Figure 2). We are currently investigating the molecular basis of genomic instability of ES and iPS cells to improve their use in regenerative medicine.

    figure 2 fr
    Figure 2. Cartoon showing how Dub3 expression controls activation of the G1/S checkpoint and the pluripotent state of mouse ES cells.
     

    Implication of translesion synthesis in the therapeutic resistance of cancer

    We have shown that ectopic expression of Rad18 in human somatic cells is sufficient to constitutively activate translesion DNA synthesis and shut down the DDR, as observed in the early embryo (Figure 3). In these conditions cells shows acquired resistance to DNA damaging agents, including those currenlty used in the clinical, such as cisplatin. We have also observed a strong expression of Rad18 in cancer stem cells of the agressive brain tumor glioblastoma, a cancer that shows an extraordinary resistance to therapy. We are currently exploring the possiblity to use Rad18 as a novel target in the treatment of this cancer whose outcome is still very poor.

    figure 3 fr
    Figure 3. Ectopic Rad18 expression in somatic mammalian cells is sufficient to induce spontaneous translesion synthesis nuclear focus formation.

    Identification of novel DDR genes

    In the aim of identifying new DDR-responsive genes, we have developped an in vitro screen using protein extracts derived from Xenopus eggs and identified five genes candidates. One of these is the Ddx19 RNA helicase, previously implicated in the export of the mRNA from the nucleus into the cytoplasm. We have shown that Ddx19 translocates from the nuclear peryphery into the nucleus upon DNA damage (Figure 4). We have also unveiled a novel nuclear function for this enzyme in the resolution of aberrant RNA:DNA hybrid structures formed upon conflicts between replication and transcription, the so called R-loops (Hodroj et al., EMBO J 2017). We are now in the process of understanding the molecular basis of this novel function for the Ddx19 helicase.

    figure 4 fr
    Figure 4. Model showing the ATR-dependent Ddx19 function in nuclear R-loop resolution.
  • Course and current status

    Since April 2007. Group leader of the "Genome Surveillance and Stability" team at the Institute of Human Genetics of Montpellier (France). Biochemistry and Cell Biology of DNA damage and replication checkpoints.
    2001. Staff researcher employed by INSERM at the CNRS Institute of Human Genetics of Montpellier (France).
    1997-2001. Postdoctoral fellow at the Institute Jacques Monod (Paris, France), then at the Institute of Human Genetics of Montpellier (France). Biochemistry of DNA replication in Xenopus in vitro systems.
    1996. Research Assistant at the University of Oxford.
    1995. PhD at the University of Oxford (England, UK). Cell cycle regulation of DNA replication in fission yeast.

    Membership

    • Member of Trinity College, Oxford (England, UK)
    • Member of Faculty of 1000 Biology “Nuclear Structure and Function Section”
    • Member of the French Society of Cell Biology
    • Biography published by Marquis “Who’s Who in the World”, “Who’s Who in Healthcare and Medicine”, “ Who’s Who in Science and Engineering”.
    • Academic editor at PloS One
    • Member of the editorial board of faculty of Faculty of 1000 Research