Radiation dose-dependent maintenance of G(2) arrest requires retinoblastoma protein.
In response to ionizing radiation (IR), cell cycle checkpoints are activated to provide time for DNA repair. Several different checkpoint mechanisms have been elucidated. However, mechanisms that regulate the duration of cell cycle arrest are not understood. Previous studies have shown that the retinoblastoma tumor suppressor protein (RB) is required for radiation-induced G1 arrest. Working with primary fibroblasts derived from Rb+/+ and Rb-/- mouse embryos, we show that RB also regulates the duration of G2 arrest. The initial G2 checkpoint response is enhanced in Rb-/- cells due to a defect in G1 arrest. However, the permanent arrest in G2 induced by higher doses of IR does not occur in Rb-/- cells. Rb-/- cells either resumed proliferation or underwent apoptosis at IR doses that caused the majority of Rb+/+ cells to arrest permanently in G2. The prolongation of G2 arrest in Rb+/+ cells correlated with a gradual accumulation of hypophosphorylated RB. Thus, regulation of the RB function may be an important aspect in the maintenance of cell cycle checkpoints in DNA damage response.
Naderi
Soheil
S
Department of Medical Biochemistry, University of Oslo, P.O. Box 1112 Blindern, Oslo N-0317, Norway. soheil.naderi@basalmed.uio.no
Hunton
Irina C
IC
Wang
Jean Y J
JY
D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle / Q000528:radiation effects*; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D015151:Immunoblotting; D007259:Infrared Rays; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D010766:Phosphorylation; D011233:Precipitin Tests; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000502:physiology*; D013997:Time Factors
D016160:Retinoblastoma Protein; D001973:Bromodeoxyuridine