title: The prion protein is critical for DNA repair and cell survival after genotoxic stress.
abstract: The prion protein (PrP) is highly conserved and ubiquitously expressed, suggesting that it plays an important physiological function. However, despite decades of investigation, this role remains elusive. Here, by using animal and cellular models, we unveil a key role of PrP in the DNA damage response. Exposure of neurons to a genotoxic stress activates PRNP transcription leading to an increased amount of PrP in the nucleus where it interacts with APE1, the major mammalian endonuclease essential for base excision repair, and stimulates its activity. Preventing the induction of PRNP results in accumulation of abasic sites in DNA and impairs cell survival after genotoxic treatment. Brains from Prnp(-/-) mice display a reduced APE1 activity and a defect in the repair of induced DNA damage in vivo. Thus, PrP is required to maintain genomic stability in response to genotoxic stresses.
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bravard
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Auvré
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Damiano
authors.initials: D
authors.lastname: Fantini
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bernardino-Sgherri
authors.affiliation: CEA, Institut des Maladies Emergentes et des Thérapies Innovantes, Service d'Etudes des Prions et des Infections Atypiques, F-92265 Fontenay-aux-roses, France.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Sissoëff
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Daynac
authors.affiliation: CEA, Institut des Maladies Emergentes et des Thérapies Innovantes, Service d'Etudes des Prions et des Infections Atypiques, F-92265 Fontenay-aux-roses, France.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xu
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Etienne
authors.affiliation: CEA, Institut des Maladies Emergentes et des Thérapies Innovantes, Service d'Etudes des Prions et des Infections Atypiques, F-92265 Fontenay-aux-roses, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Dehen
authors.affiliation: CEA, Institut des Maladies Emergentes et des Thérapies Innovantes, Service d'Etudes des Prions et des Infections Atypiques, F-92265 Fontenay-aux-roses, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Comoy
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: François D
authors.initials: FD
authors.lastname: Boussin
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, I-33100 Udine, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
authors.affiliation: CEA, Institut des Maladies Emergentes et des Thérapies Innovantes, Service d'Etudes des Prions et des Infections Atypiques, F-92265 Fontenay-aux-roses, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Deslys
authors.affiliation: CEA, Institute of Cellular and Molecular Radiobiology, F-92265 Fontenay-aux-Roses, France INSERM, U967, F-92265 Fontenay-aux-Roses, France Université Paris Diderot, UMR 967, F-92265 Fontenay-aux-Roses, France Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France pablo.radicella@cea.fr.
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Radicella
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D002470:Cell Survival; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D006801:Humans; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D009153:Mutagens; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D008741:Methyl Methanesulfonate; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase