caa a22 4500 606175865 CHVBK 20210128100745.0 cr unu---uuuuu 210128e20150901xx s 000 0 eng 10.1007/s00018-015-1901-7 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1901-7 A kinome-targeted RNAi-based screen links FGF signaling to H2AX phosphorylation in response to radiation [Elektronische Daten] [Sami Benzina, Amandine Pitaval, Claudie Lemercier, Celine Lustremant, Vincent Frouin, Ning Wu, Alexandre Papine, Françoise Soussaline, Paul-Henri Romeo, Xavier Gidrol] A general radioprotective effect by fibroblast growth factor (FGF) has been extensively described since the early 1990s; however, the molecular mechanisms involved remain largely unknown. Radiation-induced DNA double-strand breaks (DSBs) lead to a complex set of responses in eukaryotic cells. One of the earliest consequences is phosphorylation of histone H2AX to form nuclear foci of the phosphorylated form of H2AX (γH2AX) in the chromatin adjacent to sites of DSBs and to initiate the recruitment of DNA-repair molecules. Upon a DSB event, a rapid signaling network is activated to coordinate DNA repair with the induction of cell-cycle checkpoints. To date, three kinases (ATM, ATR, and DNA-PK) have been shown to phosphorylate histone H2AX in response to irradiation. Here, we report a kinome-targeted small interfering RNA (siRNA) screen to characterize human kinases involved in H2AX phosphorylation. By analyzing γH2AX foci at a single-nucleus level, we identified 46 kinases involved either directly or indirectly in H2AX phosphorylation in response to irradiation in human keratinocytes. Furthermore, we demonstrate that in response to irradiation, the FGFR4 signaling cascade promotes JNK1 activation and direct H2AX phosphorylation leading, in turn, to more efficient DNA repair. This can explain, at least partially, the radioprotective effect of FGF. The Author(s), 2015 DSB nationallicence γH2AX nationallicence FGFR4 nationallicence JNK1 nationallicence ATM nationallicence Benzina Sami CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut Pitaval Amandine CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut Lemercier Claudie CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut Lustremant Celine CEA, DSV, IRCM, 18 route du panorama, 92265, Fontenay-Aux-Roses, France aut Frouin Vincent CEA, DSV, IRCM, 18 route du panorama, 92265, Fontenay-Aux-Roses, France aut Wu Ning CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut Papine Alexandre IMSTAR, 60 rue Notre Dame-des-Champs, 75006, Paris, France aut Soussaline Françoise IMSTAR, 60 rue Notre Dame-des-Champs, 75006, Paris, France aut Romeo Paul-Henri CEA, DSV, IRCM, 18 route du panorama, 92265, Fontenay-Aux-Roses, France aut Gidrol Xavier CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut Cellular and Molecular Life Sciences Springer Basel 72/18(2015-09-01), 3559-3573 1420-682X 72:18<3559 2015 72 18 https://doi.org/10.1007/s00018-015-1901-7 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1901-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Benzina Sami CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut NATIONALLICENCE 700 1- Pitaval Amandine CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut NATIONALLICENCE 700 1- Lemercier Claudie CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut NATIONALLICENCE 700 1- Lustremant Celine CEA, DSV, IRCM, 18 route du panorama, 92265, Fontenay-Aux-Roses, France aut NATIONALLICENCE 700 1- Frouin Vincent CEA, DSV, IRCM, 18 route du panorama, 92265, Fontenay-Aux-Roses, France aut NATIONALLICENCE 700 1- Wu Ning CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut NATIONALLICENCE 700 1- Papine Alexandre IMSTAR, 60 rue Notre Dame-des-Champs, 75006, Paris, France aut NATIONALLICENCE 700 1- Soussaline Françoise IMSTAR, 60 rue Notre Dame-des-Champs, 75006, Paris, France aut NATIONALLICENCE 700 1- Romeo Paul-Henri CEA, DSV, IRCM, 18 route du panorama, 92265, Fontenay-Aux-Roses, France aut NATIONALLICENCE 700 1- Gidrol Xavier CEA, IRTSV, Biologie à Grande Echelle, 17 rue des Martyrs, 38054, Grenoble Cedex, France aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/18(2015-09-01), 3559-3573 1420-682X 72:18<3559 2015 72 18