Ubiquitin-dependent protein processing controls radiation-induced apoptosis through the N-end rule pathway.
The ubiquitination of nuclear proteins activated in human lymphocytes undergoing radiation-induced apoptosis and the subsequent downstream proteasomal protein processing, shown to be involved in apoptotic death control, may be dependent on an amino-terminal sequence identity of ubiquitin target proteins, the "N-end rule" pathway. Here we report that this selective pathway controls radiation-induced apoptosis and that it is involved in the initiation of this type of cell death. Dipeptide competitors of protein ubiquitination/processing dependent solely on the basic amino-terminal residues (type I) efficiently inhibited the radiation-induced apoptotic death phenotype, indicating that only the substrates of ubiquitination with basic NH2-terminal amino acids are involved in apoptotic death control. This selective inhibition was followed by an early, overall but also target-specific inhibition of ubiquitination and by an activation and stabilization of poly(ADP-ribose) polymerase (PARP) that occurs through inhibition of ubiquitination of its cleaved form (85 kDa). Interestingly, caspases-3 and -7 were not activated following irradiation, further suggesting that PARP cleavage may be regulated by an N-end rule pathway in a caspase-independent manner. These results highly suggest involvement of this subset of the ubiquitin system in the apoptotic death control and in the specific regulation of PARP activity.
Masdehors
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Laboratoire de Recherche Correspondant No. 2 du CEA (DSV/DRR/Fontenay Aux Roses), Paris, France.
Glaisner
S
S
Maciorowski
Z
Z
Magdelénat
H
H
Delic
J
J
D000596:Amino Acids; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D002478:Cells, Cultured; D006801:Humans; D008214:Lymphocytes / Q000473:pathology* / Q000502:physiology* / Q000528:radiation effects; D010446:Peptide Fragments; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D014452:Ubiquitins / Q000502:physiology*
D000596:Amino Acids; D010446:Peptide Fragments; D014452:Ubiquitins; D011065:Poly(ADP-ribose) Polymerases