Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation.
A nuclear poly(ADP-ribose) polymerase (PARP) is activated by gamma-irradiation and consequently synthesizes poly(ADP-ribose) by binding to DNA strand-breaks. This property suggests that PARP is a DNA strand-break-signal generator. Meanwhile, the cell-cycle arrest occurs in G1 and G2 phases following gamma-irradiation. We found that PARP inhibitors including 3-aminobenzamide (3-AB) suppressed G1 arrest and enhanced G2 arrest following gamma-irradiation. These observations suggested that PARP is critical for the induction of G1 arrest and is also involved in the regulation of G2 arrest. Furthermore, the effects of 3-AB on the G1-arrest signal-transduction pathway were also studied. We found that p53 stabilization following gamma-irradiation was not inhibited but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM-2 mRNA were suppressed by 3-AB. Therefore, it is suggested that PARP participates in G1-arrest signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM-2 mRNA expression.
Masutani
M
M
Biochemistry Division, National Cancer Center Research Institute, Tokyo, Japan.
Nozaki
T
T
Wakabayashi
K
K
Sugimura
T
T
D000818:Animals; D004249:DNA Damage; D004789:Enzyme Activation; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects*; D016195:G2 Phase / Q000528:radiation effects*; D005720:Gamma Rays; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology* / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; D011065:Poly(ADP-ribose) Polymerases