title: G0 cell cycle arrest alone is insufficient for enabling the repair of ionizing radiation-induced potentially lethal damage.
abstract: The repair of ionizing radiation-induced potentially lethal damage (PLD) is suggested to be important for the clinical response to radiotherapy. PLD repair is usually studied in quiescent cultures prepared by growing cells to confluence with an accumulation of cells in G(0) phase of the cell cycle, but the biological pathways enabling PLD repair are still unknown. In this study, we examined whether the controlled expression of two different inducers of G(0) cell cycle arrest, the human tumor suppressor gene growth arrest specific 1 (GAS1) in murine fibroblasts and the forkhead transcription factor FOXO3a in human colon carcinoma cells, is sufficient to enable PLD repair. We found that GAS1 and FOXO3a induced a cell cycle arrest in G(0) phase with a concomitant reduction of proliferation of log-phase cells. In both cell systems, this cell cycle arrest in G(0) phase did not enable PLD repair in log-phase cells. Significant PLD repair was found in all confluent cultures that showed similar cell cycle distributions, while GAS1 and FOXO3a in confluent cells did not influence PLD repair. No differences were found in cell cycle re-entry after replating cells with different capacities for PLD repair. Our data suggest that the induction of G(0) cell cycle arrest and the reduction of proliferation are not sufficient to enable PLD repair.
authors.affiliation: Academic Medical Center, Laboratory for Experimental Oncology and Radiobiology, Department of Radiation Oncology, University of Amsterdam, Amsterdam, The Netherlands. c.vanbree@amc.uva.nl
authors.forename: Chris
authors.initials: C
authors.lastname: van Bree
authors.forename: Hans M
authors.initials: HM
authors.lastname: Rodermond
authors.forename: Rosemarie
authors.initials: R
authors.lastname: ten Cate
authors.forename: Judith
authors.initials: J
authors.lastname: de Vos
authors.forename: Lukas J A
authors.initials: LJ
authors.lastname: Stalpers
authors.forename: Jaap
authors.initials: J
authors.lastname: Haveman
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.forename: Nicolaas A P
authors.initials: NA
authors.lastname: Franken
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology* / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D058851:GPI-Linked Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011829:Radiation Dosage; D016192:Resting Phase, Cell Cycle / Q000502:physiology* / Q000528:radiation effects*
chemical_list: D018797:Cell Cycle Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D008565:Membrane Proteins