Genetic Instability and Cancer

 Angelos CONSTANTINOU

 IGH - UMR 9002

 141, rue de la Cardonille, 34396 Montpellier

Phone: +33 4 34 35 98 14

Email: angelos.constantinou@igh.cnrs.fr

Website

Cancer cells are characterized by replication-associated chromosomal instability. Our objective is to unveil key mechanisms that overcome replication obstacles during cancer cell proliferation. We believe that these mechanisms are key determinants of tumour growth and resistance to chemotherapies. To achieve this goal, we explore biochemical principles that underlie the signaling of DNA replication obstacles. Using proteomic approaches, we analyze systematically the composition of replication factories in basal conditions and in response to a variety of replication inhibitors used in chemotherapies. Last, we study the function of proteins implicated in Fanconi anemia, a chromosomal instability syndrome associated with congenital abnormalities, bone marrow failure and cancer proneness.

Keywords: Cancer; DNA damage response; DNA replication stress; Fanconi anemia; DNA repair.

Main publications

• Moriel-Carretero M, Ovejero S, Gérus-Durand M, Vryzas D, and Constantinou A. (2017). Fanconi anemia FANCD2 and FANCI proteins regulate the nuclear dynamics of splicing factors. The Journal of Cell Biology; 2017, 216 (12) 4007-4026; DOI: 10.1083/jcb.201702136.
• 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). RecQ1 helicase is involved in replication stress survival and drug resitance in multiple myeloma. Leukemia, 2017 Oct;31(10):2104-2113. doi: 10.1038/leu.2017.
• Ribeyre, C., Zellweger, R., Chauvin, M., Bec,N., Larroque, C.,  Massimo Lopes, M., and Constantinou, A. (2016). Nascent Dna proteomics reveals a chromatin remodeler required for topoisomerase I loading at replication forks. Cell Reports, 2016 Apr 12;15(2):300-9. doi: 10.1016/j.celrep.2016.03.027.
• Alsafadi, S., Houy, A., Battistella, A., Popova, T., Wassef, M., Emilie Henry, E., Tirode, F., Constantinou, A., Piperno-Neumann, S., Roman-Roman, S., Dutertre, M., and Stern, M-H. (2016). Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nature Communications, 2016 Feb 4;7:10615. doi: 10.1038/ncomms10615.
• Bret C, Klein B, Cartron G, Schved JF, Constantinou A, Pasero P, Moreaux J. (2015). DNA repair in diffuse large B-cell lymphoma: a molecular portrait. Br J Haematol. 2015 Apr;169(2):296-9. doi: 10.1111/bjh.13206.
• Kassambara A, Gourzones-Dmitriev C, Sahota S, Rème T, Moreaux J, Goldschmidt H, Constantinou A, Pasero P, Hose D, Klein B (2014). A DNA repair pathway score predicts survival in human multiple myeloma: the potential for therapeutic strategy. Oncotarget. 2014 May 15;5(9):2487-98.
• Laguette, N., Brégnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., Kirchhoff, F., Constantinou, A., Sobhian, B., Benkirane, M. (2014). Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing. Cell, Jan 16; 156(1-2):134-45.doi:10.1016/j.cell.2013.12.011.
• Gourzones-Dmitriev, C., Kassambara, A., Sahota, S., Rème, T., Moreaux, J., Bourquard, P., Dirk Hose, D., Pasero, P., Constantinou, A., Klein, B. (2013). DNA repair pathways in human multiple myeloma: Role in oncogenesis and potential targets for treatment. Cell Cycle, Cell Cycle. 2013 Sep 1;12(17):2760-73. doi: 10.4161/cc.25951.
• Lossaint, G., Larroque, M., Ribeyre, C., Bec, N., Larroque, C., Décaillet, C., Gari, K., and Constantinou, A. (2013). FANCD2 Binds MCM Proteins and Controls Replisome Function upon Activation of S Phase 20. Checkpoint Signaling. Molecular Cell, 51(5):678-90. doi: 10.1016/j.molcel.2013.07.023.
• Vidal-Eychenie, S., Decaillet, C., Basbous, J., and Constantinou, A. (2013). DNA structure-specific priming of ATR activation by DNA-PKcs. The Journal of Cell Biology, 202.