The onset of p53-dependent DNA repair or apoptosis is determined by the level of accumulated damaged DNA.
The p53 tumor suppressor gene plays an important role in both apoptosis and DNA repair pathways that are pivotal for genomic stability. Here we show that the treatment of cells with low doses of gamma-irradiation or cisplatin resulted in an immediate enhancement of p53-dependent DNA repair, measured by base excision repair (BER) activity. However, treatment of cells with high doses of DNA damaging agents resulted in a reduction in p53-dependent DNA repair and in the induction of p53-dependent apoptosis. Analysis of p53 upstream molecular events suggested that regulation of p53-associated DNA repair is ATM-dependent. Furthermore, we observed that while dephosphorylation of Ser376 at the C-terminus of the p53 protein was associated with enhancement in DNA repair, phosphorylation at the N-terminal Ser15 resulted in the reduction in DNA repair. The latter is also in correlation with an enhancement in the specific DNA binding activity and in the induction of apoptosis. Treatment of cells with a caspase inhibitor, prior to the damaging agent-blocked apoptosis, had no effect on the DNA repair pattern. Taken together, this suggests that the decision of cells to induce a p53-dependent DNA repair or apoptosis is most probably controlled by the level of genotoxic agent introduced to cells.
Offer
Hagai
H
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Erez
Neta
N
Zurer
Irit
I
Tang
Xiaohu
X
Milyavsky
Michael
M
Goldfinger
Naomi
N
Rotter
Varda
V
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D005720:Gamma Rays; D016158:Genes, p53; D051379:Mice; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D002945:Cisplatin