DNA As a Sensor of Oncogenic Threat
18 Jan, 2007 06:14 pm
DNA has been the focus of biomedical research since the discovery of its structure by Watson and Crick in 1953. DNA is portrayed as the essence of life, the container of all the information that makes living organisms. It is then not surprising that organisms have evolved efficient machineries to detect damage in the DNA and repair it. Recent results from our laboratory at the University of Montreal add an interesting twist to the DNA paradigm: the system that detects and deals with DNA damage allows the detection of oncogenic activity in normal cells and organize an efficient anti-oncogenic response known as cellular senescence.
To look into this general problem we decided to compare the response of normal cells to different oncogenic stresses. We chose oncogenic ras, E2F1 and STAT5A as model oncogenes. The Ras gene is mutated and active in 30% of human cancers, and more than 90% of pancreatic cancers. E2F1 is perhaps hyperactivated in most human cancers, and STAT5 is active in many leukemias, breast cancer, prostate cancer and head and neck cancer. More important, Ras activates growth factor signaling pathways while E2F1 and STAT5 are transcription factors that stimulate non-overlapping gene expression patterns. Despite the biochemical differences between these oncogenes, the three of them induced signals of DNA damage in normal cells suggesting that the DNA itself was the ultimate sensor of the oncogenic threat. These DNA damage signals were critical to implement the antiproliferative response to the oncogenes because inactivation of the DNA damage activated kinase ATM using RNA interference abrogated the senescent growth arrest induced by these oncogenes. The mechanism by which oncogenes cause DNA breaks is still unclear, but one theory proposes that oncogenes increase cell metabolism and the generation of reactive oxygen species. The latter can induce oxidative DNA damage and DNA breaks.
The new data, together with similar results published in Nature by the groups of d’Adda di Fagagna and Gorgoulis implicates DNA damage as the central mediator of the recognition of the oncogenic stress. As a consequence, in addition to coding for all the information required to built and maintain life, DNA may play a role as a sensor of the health of the cell including its oncogenic potential. In addition, these findings suggest ideas for early detection of malignant lesions and may help to design strategies to prevent their progression.