Postdoctoral Research Position Structural studies and inhibitors design of NHEJ pathway
A 24 month postdoctoral position is available in the Laboratory of Structural Biology and Radiobiology. The group, led by Jean-Baptiste Charbonnier, is located at the CEA Saclay (South Paris) and is part of the I2BC (Institute of Integrated Biology of the Cell) (http://www.i2bc.paris-saclay.fr/). Our team investigates the structural and functional studies of DNA repair machineries. We produce, crystallize and determine the 3D structure of complexes involved in DNA repair. We reported the crystal structure of the XRCC4-Cernunnos/XLF complex and identified a filament organization of this complex (Ropars, 2011, PNAS; Malivert, 2010, J Biol Chem). We combine in our studies, X-ray crystallography, molecular modeling, protein-protein interaction measurements and SAXS. We recently implemented robust protocols for the production in insect cells, with the MultiBac approach, of 6 core factors of the human NHEJ pathway: Ku70/Ku80, Artemis, Ligase4-XRCC4 and Cernunnos. Our first aim is to crystallize multi-protein complexes involving combination of these NHEJ factors and DNA substrates. To guide our crystallization, we characterize the stability of our multi-protein complexes with a large set-up of biochemical and biophysical methods. Our second major aim is to identify and characterize potent inhibitors of the NHEJ pathway for new anti-cancer treatments. For that, we combine structure-based drug design, small molecules screenings, X-ray structure of protein-inhibitor complexes and tight collaboration with DNA repair biologists. Our group is part of the Institute of Integrative Biology of the Cell (I2BC). The I2BC is a mixed research unit supported by the Paris-Sud University, the CNRS and the CEA. The Institute regroups 80 teams of scientists and 15 technological facilities including state-of-the-art equipment in high-throughput crystallization, NMR, EM, super-resolution microscopy, protein-protein interactions, insect cells expression and mass spectrometry. The Institute is in 3 research campus (Orsay Campus of the Univ Paris Sud University, Gif Sur Yvette Campus of CNRS, and Saclay Campus of CEA) with 14 buildings. All the I2BC activities will be joined on the Gif Sur Yvette Campus in 2018. The I2BC generates an excellent scientific environment for high quality and intensive scientific life. Group meetings, external and internal seminars in the Institute are in English. Saclay is 30min south Paris by public transports. We are seeking highly motivated and skilled researchers with broad and extensive experience within one or more of the following areas: DNA Repair, Crystallization, Crystallography, Protein Expression of proteins in insect cells (or E. Coli), Cellular biology, Protein interaction measurements, SAXS, EM. The position is available immediately. Applications should be sent no later than end of June, including motivation letter, CV, summary of research experience and contacts for references to: jb.charbonn...@cea.fr<mailto:jb.charbonn...@cea.fr> (http://www.i2bc.paris-saclay.fr/spip.php?article168) Ropars V (2011) Structural characterization of filaments formed by human (2011) Xrcc4-Cernunnos/XLF complex involved in nonhomologous DNA end-joining. Proc Natl Acad Sci U S A. 108(31):12663-8 Malivert L (2010) Delineation of the Xrcc4-interacting region in the globular head domain of cernunnos/XLF. (2010) J Biol Chem. 2010 285(34):26475-83 de Villartay JP (2009) A histidine in the beta-CASP domain of Artemis is critical for its full in vitro and in vivo functions. DNA Repair (Amst). 8(2):202-8 Guarné (2015) A Insights from a decade of biophysical studies on MutL: Roles in strand discrimination and mismatch removal (2015) Prog Biophys Mol Biol. 117(2-3):149-156. Meurisse J (2014) Hug1 is an intrinsically disordered protein that inhibits ribonucleotide reductase activity by directly binding Rnr2 subunit. (2014) Nucleic Acids Res. 42(21):13174-85 Bacquin A, (2013) The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells. Nucleic Acids Res. 2013 41(13):6501-13 Gueneau E, (2013) Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site. Nat Struct Mol Biol. 2013 20(4):461-8.
