Abstract
The tumour supressor protein p53 plays a key role in the cell's decision to arrest the cell cycle or undergo apoptosis following a genotoxic insult. p53 is stabilized and activated after DNA damage, however the cascade of events signalling from DNA lesions to p53 stabilization and activation is still controversial. Poly (ADP-ribosylation) of different nuclear acceptors by PARP-1 is an early event when a single strand DNA lesion is produced. We present here evidences that interplay between PARP-1 and p53 is dependent on the type of damage induced to DNA. Primary mouse embryonic fibroblasts derived from parp-1−/− mice exhibited decreased p53 accumulation and activation following γ-irradiation compared to parp-1 proficient cells. On the other hand, treatment with the single alkylating agent 2′-methyl-2′-nitrose-urea (MNU), resulted in the rapid and sustained accumulation and activation of p53 in parp-1-deficient cells, while very little accumulation was observed in parp-1+/+ cells. After IR, the turnover of the p53 inhibitory protein MDM-2 is perturbed and the level of phosphorylation of p53 at serine-15 is blunted in parp-1−/− cells. PARP-1 is determinant in the cytotoxic response to alkylating agents but only partially contributes to radiation-induced cell killing, as determined by colony forming assay. Altogether, these results suggest that PARP-1 participates in the p53 response following irradiation, resides upstream of p53 and indirectly modulates the level of phosphorylation of key substrates in this pathway while treatment with MNU results in an enhanced p53-mediated response in parp-1-null cells.
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Acknowledgements
This work was supported by a Grant from the Fondo de Investigación Sanitarias through the project FIS 00/0948 to FJ Oliver and by the Comisión Interministerial de Ciencia y Tecnología through the project PM97-0185 to JM Ruiz de Almodóvar. MT Valenzuela (009371) and R Guerrero are supported by fellowships from Fondo de Investigación Sanitaria (BEFI) and Instituto de Salud Carlos III, respectively. We are also indebted to Dr Josiane Ménissier- de-Murcia and Dr Abelardo López-Rivas for helpful discussion and reviewing of the manuscript and to Carmen Conde and Guadalupe de la Rubia for their excellent help in getting primary cells.
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Valenzuela, M., Guerrero, R., Núñez, M. et al. PARP-1 modifies the effectiveness of p53-mediated DNA damage response. Oncogene 21, 1108–1116 (2002). https://doi.org/10.1038/sj.onc.1205169
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DOI: https://doi.org/10.1038/sj.onc.1205169
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