Genetic Instability and Cancer

  • From the earliest stages of tumorigenesis, deregulated oncogenes induce the formation of DNA lesions during the process of DNA replication. Stalled replication forks and chemical alterations in DNA induce a variety of surveillance pathways collectively known as the DNA damage response. Our knowledge of DNA damage signalling and DNA repair mechanisms is well documented by studies that use high doses of laser micro-irradiation, ionizing radiations or endonucleases to induce double-strand DNA breaks in DNA. By contrast, very little is known about how cells respond to DNA replication impediments induced by normal physiological processes such as transcription.

    Our objective is to unveil key mechanisms that promote DNA replication under stressful conditions. We believe that these mechanisms are key determinants of tumour growth and resistance to chemotherapies. We use proteomic approaches to understand the biology of the replication machinery under stressful conditions.

    We explore novel mechanisms implicated in the signalling of DNA replication stress using an ATR signalling system whereby a defined DNA structure containing a single-stranded DNA gap is used to nucleate, in human cell-free extracts, a singularly active ATR signalling complex that promotes the phosphorylation of endogenous Chk1. We exploit this original system to work out the biochemical principles that underlie the self-assembly and activation of the ATR signalling complex.

    We have analysed systematically the composition of replication factories in basal conditions and in response to a variety of replication inhibitors used in chemotherapies. Proteins that determine replication stress responses using different criteria are studied using a combination of biochemical, cell biochemical and DNA fiber labelling approaches.

    In recent years, our main focus has been on the molecular function of proteins implicated in Fanconi anaemia, a genetic disorder characterised by congenital abnormalities, bone marrow failure and cancer proneness. FANC proteins are necessary to coordinate the action of molecular machines involved in the rescue of stalled replication forks and in DNA repair.


    Members

    Jihane Basbous
    Basbous Jihane
    Angelos Constantinou
    Constantinou Angelos
    Cyril Ribeyre
    Ribeyre Cyril
    Sophie Vidal-eychenie
    Vidal-eychenie Sophie
    Alexy Promonet
    Promonet Alexy
    Camilla Frattini
    Frattini Camilla
    Emile Alghoul
    Alghoul Emile
    Gaël Dupin
    Dupin Gaël
    Rana Lebdy
    Lebdy Rana

    Publications

    Nascent DNA Proteomics Reveals a Chromatin Remodeler Required for Topoisomerase I Loading at Replication Forks

    Ribeyre C, Zellweger R, Chauvin M, Bec N, Larroque C, Lopes M, Constantinou A

    2016 - Cell Rep, 15, 2, 300-309

    Download publication27050524

    A tumor suppressive DNA translocase named FANCM.

    Basbous J, Constantinou A

    2019 - Crit Rev Biochem Mol Biol, :1-14

    Request for full article30714416

    Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling.

    Kumbhar R, Vidal-Eychenié S, Kontopoulos DG, Larroque M, Larroque C, Basbous J, Kossida S, Ribeyre C, Constantinou A

    2018 - Life Sci Alliance, 1(3):e201800096

    Request for full article30456359

    RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma

    Viziteu E, Klein B, Basbous J, Lin YL, Hirtz C, Gourzones C, Tiers L, Bruyer A, Vincent L, Grandmougin C, Seckinger A, Goldschmidt H, Constantinou A, Pasero P, Hose D, Moreaux J.

    2017 - Leukemia, 31, 10, 2104-2113

    Request for full article28186131
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