title: Synchrotron photoactivation of cisplatin elicits an extra number of DNA breaks that stimulate RAD51-mediated repair pathways.
abstract: Combination of cis-platinum with ionizing radiation is one of the most promising anticancer treatments that appears to be more efficient than radiotherapy alone. Unlike conventional X-ray emitters, accelerators of high energy particles like synchrotrons display powerful and monochromatizable radiation that makes the induction of an Auger electron cascade in cis-platinum molecules [also called photoactivation of cis-platinum (PAT-Plat)] theoretically possible. Here, we examined the molecular consequences of one of the first attempts of synchrotron PAT-Plat, performed at the European Synchrotron Research Facility (Grenoble-France). PAT-Plat was found to result in an extra number of slowly repairable DNA double-strand breaks, inhibition of DNA-protein kinase activity, dramatic nuclear relocalization of RAD51, hyperphosphorylation of the BRCA1 protein, and activation of proto-oncogenic c-Abl tyrosine kinase.
authors.affiliation: Equipe d'Accueil 2941 Rayonnement Synchrotron et Recherche Médicale, Unité IRM, CHU A. Michallon, BP 217, F-38043 Grenoble cedex 09, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Corde
authors.forename: Jacques
authors.initials: J
authors.lastname: Balosso
authors.forename: Hélène
authors.initials: H
authors.lastname: Elleaume
authors.forename: Michel
authors.initials: M
authors.lastname: Renier
authors.forename: Aurélie
authors.initials: A
authors.lastname: Joubert
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Biston
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Adam
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Charvet
authors.forename: Thierry
authors.initials: T
authors.lastname: Brochard
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Le Bas
authors.forename: François
authors.initials: F
authors.lastname: Estève
authors.forename: Nicolas
authors.initials: N
authors.lastname: Foray
mesh_terms: D021581:Active Transport, Cell Nucleus; D019313:BRCA1 Protein / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology / Q000528:radiation effects*; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000502:physiology*; D004583:Electrons; D016521:Electrophoresis, Gel, Pulsed-Field; D004789:Enzyme Activation; D005240:Feasibility Studies; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D006258:Head and Neck Neoplasms / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000502:physiology; D009687:Nuclear Proteins; D010777:Photochemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051135:Rad51 Recombinase; D017356:Synchrotrons
chemical_list: D019313:BRCA1 Protein; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016315:Proto-Oncogene Proteins c-abl; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin