Cell-cycle arrest activated by DNA-damage response (DDR) signalling pathways and oncogene-induced senescence (OIS) is thought to function as a barrier to tumorigenesis. The mechanisms by which DDR signalling and OIS are activated and whether they are causally related has remained unclear. Fabrizio d'Adda di Fagagna and colleagues, and Thanos Halazonetis, Jiri Bartek and colleagues now show that the efficient activation of DDR signalling is necessary to activate and maintain OIS.

The groups show that overexpression of the oncogenes MOS , CDC6 , CCNE1 (which encodes cyclin E) and activated HRAS in human fibroblast cell lines results in OIS. Cells that showed features of OIS correlated with the activation of two key DDR signalling pathways that involve the kinases ataxia-telangiectasia and rad3-related (ATR) and ataxia-telangiectasia mutated (ATM). Inhibition of ATR-dependent and ATM-dependent DDR pathway members, such as CHK2, p53 and ATM itself, abrogated OIS in these cells, indicating that efficient DDR pathway activation is required for the establishment and maintenance of OIS. This was confirmed in vivo when immunodeficient mice injected with Chk2−/− mouse embryonic fibroblasts (MEFs) that overexpressed activated Hras formed tumours, unlike those injected with wild-type MEFs that expressed activated Hras. Larger and more invasive tumours were also observed when immunodeficient mice were injected with PDVC57 mouse tumour cells in which ATM was inhibited.

So, what type of DNA damage activates DDR signalling during OIS? The groups show that cells that overexpressed MOS, CDC6, CCNE1 or activated HRAS placed in non-replicative conditions did not activate DDR signalling pathways or undergo OIS. Additionally, d'Adda di Fagagna and colleagues show that activated HRAS overexpression leads to DNA hyper-replication, followed by the activation of DDR signalling pathways and then OIS. Both groups show that DNA damage occurs in replicating cells, in which oncogene overexpression results in aberrant replication dynamics and replication-fork instability. Consequently, DNA strand breaks occur, which lead to genomic instability and the activation of ATM-dependent and ATR-dependent DDR signalling pathways.

Is this relevant to cancer in vivo? Halazonetis, Bartek and colleagues used frozen tissue sections of colon cancer and bladder cancer to show that premalignant tissues associated with these cancers have activated DDR signalling, and that this correlates with OIS. However, in samples derived from progressive disease (such as colon carcinoma compared with colon adenoma), the activation of DDR signalling and OIS were decreased. Moreover, using a mouse model of skin carcinogenesis, the groups show that DDR signalling and OIS could be detected in benign skin papillomas as opposed to adjacent normal tissue.

These authors have uncovered one of the molecular pathways that lead to OIS. They propose a model of tumorigenesis wherein premalignant tissues that overexpress cancer-type-specific oncogenes undergo hyperproliferation and accumulate replication-dependent DNA damage. This results in the activation of ATR-dependent and ATM-dependent DDR signalling pathways. Active DDR signalling is necessary for OIS and possibly apoptosis, providing barriers to the tumorigenic pathway. This model could provide a common mechanism for tumorigenesis, with implications for anticancer drug development and patient treatment.