title: Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.
abstract: Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.
authors.affiliation: Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark. jb@cancer.dk
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Nousin
authors.initials: N
authors.lastname: Rezaei
authors.forename: Michalis
authors.initials: M
authors.lastname: Liontos
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karakaidos
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kletsas
authors.forename: Natalia
authors.initials: N
authors.lastname: Issaeva
authors.forename: Leandros-Vassilios F
authors.initials: LV
authors.lastname: Vassiliou
authors.forename: Evangelos
authors.initials: E
authors.lastname: Kolettas
authors.forename: Katerina
authors.initials: K
authors.lastname: Niforou
authors.forename: Vassilis C
authors.initials: VC
authors.lastname: Zoumpourlis
authors.forename: Munenori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: Kasper
authors.initials: K
authors.lastname: Fugger
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Claus L
authors.initials: CL
authors.lastname: Andersen
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjot
authors.forename: Torben
authors.initials: T
authors.lastname: Ørntoft
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Christos
authors.initials: C
authors.lastname: Kittas
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Thanos D
authors.initials: TD
authors.lastname: Halazonetis
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Vassilis G
authors.initials: VG
authors.lastname: Gorgoulis
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004247:DNA; D004249:DNA Damage; D004261:DNA Replication; D016258:Genes, mos; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D009857:Oncogenes; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology
chemical_list: C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D004247:DNA