Publication year: 2012
Source: Cancer Letters, Available online 16 January 2012
Wynand P. Roos, Bernd Kaina
DNA damaging agents are potent inducers of cell death triggered by apoptosis. Since these agents induce a plethora of different DNA lesions, it is firstly important to identify the specific lesions responsible for initiating apoptosis before the apoptotic executing pathways can be elucidated. Here, we describe specific DNA lesions that have been identified as apoptosis triggers, their repair and the signaling provoked by them. We discuss simple methylating agents such as temozolomide, ionizing radiation and cisplatin, all of them are important in cancer therapy. We show that the potentially lethal events for the cell are O-methylguanine adducts that are converted by mismatch repair into DNA double-strand breaks (DSB), bulky adducts that prevent the replication of DNA and directly induced DSB following ionising radiation. Sensor systems recognizing the damage and relaying the signal via kinases to executors, which evoke a process that inhibits cell cycle progression and provokes DNA repair or, if this fails, induces apoptosis. The main DNA damage recognition factor MRN and ATM, ATR and DNA-PK, which phosphorylate a multitude of proteins and thus induce the DNA damage response (DDR), will be discussed as well as the downstream players p53, NF-kB, Akt and survivin. We review data and models describing the signaling from DNA damage to the apoptosis executing machinery and discuss the complex interplay between cell survival and death.
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