1. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark
2. The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA
3. Department of Histology and Embryology, School of Medicine, University of Athens, GR-11527 Athens, Greece
4. Institute of Biology, Demokritos National Center for Scientific Research, GR-15310 Athens, Greece
5. Department of Genetics, Microbiology and Toxicology, Stockholm University, S-10691 Stockholm, Sweden
6. Department of Physiology, School of Medicine, University of Ioannina, GR-45110 Ioannina, Greece
7. Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, GR-11635 Athens, Greece
8. Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-2144, USA
9. Department of Pathology, University Hospital, DK-2100 Copenhagen, Denmark
10. Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, DK-8200 Aarhus N, Denmark
11. The Institute for Cancer Studies, University of Sheffield, Sheffield S10 2RX, UK
12. Department of Molecular Biology, University of Geneva, CH-1211 Geneva 4, Switzerland
13. These authors contributed equally to this work.

Correspondence to: Jirina Bartkova^1,13,13Thanos D. Halazonetis^2,12Jiri Bartek¹ Correspondence and requests for materials should be addressed to T.D.H. (Email: Thanos.Halazonetis@molbio.unige.ch) or J.B. (Email: 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^{1, 2}, whereas a second barrier is mediated by oncogene-induced senescence^{3, 4, 5, 6}. 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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