DNA damage signaling and p53 regulation

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The genomic integrity of our cells is continously challenged by DNA damage. DNA damage originates both from intrinsic and extrinsic sources and has been directly linked to increased genome instability, which is the major driving force for cancer development. In addition, the therapeutic response of state-of-the-art cancer therapy (such as radiation- and chemotherapy) is based on activation of the DNA damage response (DDR) and subsequent cancer cell inactivation through the cell death or senescense responses. The DDR is regulated by a complex signal transduction network involving the DNA damage-activated protein kinases ATM, ATR and HIPK2. A main focus of our work is to elucidate the signaling pathways and molecular mechanisms by which cells decide between cell death and cell survival upon DNA damage (Matt & Hofmann 2016).

Tumor suppressor p53, the most frequently mutated gene in human cancer, is activated upon DNA damage and plays a central role in DNA damage-induced cell fate control towards cell survival or cell death. The molecular mechanisms underlying these opposing p53 functions are largely unclear. Our research is aimed at identifying and characterising novel regulators of the DDR and p53 function to better understand cancer cell responsiveness to therapy (Bitomsky et al., 2013; Conrad et al., 2015; click here for further details). Our ultimate goal is to develop strategies to switch DNA damage-induced cell fate decisions in cancer cells towards the cell death response.

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