Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.
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.
Bartkova
Jirina
J
Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark. jb@cancer.dk
Rezaei
Nousin
N
Liontos
Michalis
M
Karakaidos
Panagiotis
P
Kletsas
Dimitris
D
Issaeva
Natalia
N
Vassiliou
Leandros-Vassilios F
LV
Kolettas
Evangelos
E
Niforou
Katerina
K
Zoumpourlis
Vassilis C
VC
Takaoka
Munenori
M
Nakagawa
Hiroshi
H
Tort
Frederic
F
Fugger
Kasper
K
Johansson
Fredrik
F
Sehested
Maxwell
M
Andersen
Claus L
CL
Dyrskjot
Lars
L
Ørntoft
Torben
T
Lukas
Jiri
J
Kittas
Christos
C
Helleday
Thomas
T
Halazonetis
Thanos D
TD
Bartek
Jiri
J
Gorgoulis
Vassilis G
VG
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
C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D004247:DNA