PARP-1 modifies the effectiveness of p53-mediated DNA damage response.
The tumour suppressor 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 gamma-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.
Valenzuela
M Teresa
MT
Unidad Mixta de Investigaciones Médicas, Hospital Universitario San Cecilio, Facultad de Medicina, Universidad de Granada, 18012-Granada, Spain.
Guerrero
Rosario
R
Núñez
M Isabel
MI
Ruiz De Almodóvar
J Mariano
JM
Sarker
Malabika
M
de Murcia
Gilbert
G
Oliver
F Javier
FJ
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D005720:Gamma Rays; D007700:Kinetics; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009687:Nuclear Proteins; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000477:Alkylating Agents; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D008770:Methylnitrosourea; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases