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Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Authors:Bartkova Jirina  Rezaei Nousin  Liontos Michalis  Karakaidos Panagiotis  Kletsas Dimitris  Issaeva Natalia  Vassiliou Leandros-Vassilios F  Kolettas Evangelos  Niforou Katerina  Zoumpourlis Vassilis C  Takaoka Munenori  Nakagawa Hiroshi  Tort Frederic  Fugger Kasper  Johansson Fredrik  Sehested Maxwell  Andersen Claus L  Dyrskjot Lars  Ørntoft Torben  Lukas Jiri  Kittas Christos  Helleday Thomas  Halazonetis Thanos D  Bartek Jiri  Gorgoulis Vassilis G
Institution:Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark. jb@cancer.dk
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.
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