An Oncogene-Induced DNA Damage Model for Cancer Development
Activated oncogenes disrupt normal proliferation, triggering replication stress, leading to DNA damage that stimulates the DNA damage response (DDR) pathway. Subsequently, DDR mobilizes the anti-tumor barriers of apoptosis and senescence.
As DNA damage accumulates, the cells’ capacity to repair in an error-free manner is overwhelmed, shifting repair to error-prone routes. The later fuels genomic instability, promoting cancer progression (1, 2, 3). Within this context, we have shown that DDR activation precedes ARF induction (4) and that ATM, a pivotal DDR upstream kinase, keeps in check ARF as a back-up anti-tumor response (5).
1) Gorgoulis et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 2005, 434(7035): 907-13.
2) Bartkova et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 2006, 444(7119): 633-7.
3) Halazonetis et al. An oncogene-induced DNA damage model for cancer development. Science 2008, 319(5868): 1352-5.
4) Evangelou et al. The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis. Cell Death Differ 2013, 20(11):1485-97.
5) Velimezi et al. Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer. Nat Cell Biol 2013, 15(8): 967-77.
