Impact of HIPK2 and posttranslational p53 modification on B[a]P/BPDE induced cell death and senescence

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Genotoxic stress causes DNA damage that might lead to the accumulation of mutations and carcinogenesis. To counteract these effects, DNA repair mechanisms have evolved in order to remove or tolerate DNA lesions. Besides DNA repair, additional mechanisms involved in protection against carcinogenesis exist. These are the induction of cell death via apoptosis and necrosis, transient cell cycle arrest providing time for proper repair and the induction of “irreversible” cell cycle arrest in form of senescence. A problem in predicting the outcome of an exposure to genotoxic stress is based on the fact, that all pathways can be activated separately or simultaneously, depending on the amount of stress.In our previous work, we showed that at non-toxic concentrations of the environmental carcinogen benzo(a)pyrene (B[a]P) and its active metabolite benzo(a)pyrene 9,10-diol-7,8-epoxide (BPDE), induces a p53-dependend transcriptional activation of the nucleotide excision repair and a p53/p21-mediated transcriptional repression of mismatch repair and homologous recombination, as well as induction of senescence. Whereas these mechanisms are only observed at non-toxic concentrations, activation of p53 and induction of several p53 dependent pro-apoptotic factors is observed at non-toxic and toxic concentrations. Interestingly, at non-toxic concentrations, p53 mediates survival and senescence, whereas at toxic concentrations it mediates cell death. While the initial activation of the DNA damage response does not differ between toxic and non-toxic concentrations, at later time points toxic concentrations cause a change in the DNA damage response, which now leads to cell death. Overall, these findings suggest the existence of specific thresholds at which the p53-dependent pro-survival signalling turns into pro-death signalling. The main focus of this project is to identify the molecular mechanisms by which the DNA damage response is changed and to elucidate whether the threshold for saturated DNA repair correlates to the threshold representing the switch from pro-survival signalling into pro-death signalling. Thus, we will focus on the role of posttranslational modification of p53 and the role of the protein kinase HIPK2 in the decision between live and death upon B[a]P/BPDE exposure.