1 Department of clinical biochemistry, Faculty of Health Sciences, Aarhus University, Aarhus University2 Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark3 The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA4 Department of Histology and Embryology, School of Medicine, University of Athens, GR-11527 Athens, Greece5 Institute of Biology, Demokritos National Center for Scientific Research, GR-15310 Athens, Greece6 Department of Genetics, Microbiology and Toxicology, Stockholm University, S-10691 Stockholm, Sweden7 Department of Physiology, School of Medicine, University of Ioannina, GR-45110 Ioannina, Greece8 Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, GR-11635 Athens, Greece9 Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-2144, USA10 Department of Pathology, University Hospital, DK-2100 Copenhagen, Denmark11 Department of Clinical Medicine - Molekylær Medicinsk afdeling (MOMA), Department of Clinical Medicine, Health, Aarhus University12 Department of Clinical Medicine - Molekylær Medicinsk afdeling (MOMA), Department of Clinical Medicine, Health, Aarhus University
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.