title: A role for homologous recombination and abnormal cell-cycle progression in radioresistance of glioma-initiating cells.
abstract: Glioblastoma multiforme (GBM) is the most common form of brain tumor with a poor prognosis and resistance to radiotherapy. Recent evidence suggests that glioma-initiating cells play a central role in radioresistance through DNA damage checkpoint activation and enhanced DNA repair. To investigate this in more detail, we compared the DNA damage response in nontumor forming neural progenitor cells (NPC) and glioma-initiating cells isolated from GBM patient specimens. As observed for GBM tumors, initial characterization showed that glioma-initiating cells have long-term self-renewal capacity. They express markers identical to NPCs and have the ability to form tumors in an animal model. In addition, these cells are radioresistant to varying degrees, which could not be explained by enhanced nonhomologous end joining (NHEJ). Indeed, NHEJ in glioma-initiating cells was equivalent, or in some cases reduced, as compared with NPCs. However, there was evidence for more efficient homologous recombination repair in glioma-initiating cells. We did not observe a prolonged cell cycle nor enhanced basal activation of checkpoint proteins as reported previously. Rather, cell-cycle defects in the G(1)-S and S-phase checkpoints were observed by determining entry into S-phase and radioresistant DNA synthesis following irradiation. These data suggest that homologous recombination and cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and that both processes may be suitable targets for therapy.
authors: Queensland Institute of Medical Research, University of Queensland Centre for Clinical Research, Royal Brisbane Hospital Campus, Herston, Queensland, Australia.
authors: Yi Chieh
authors: YC
authors: Lim
authors: Tara L
authors: TL
authors: Roberts
authors: Bryan W
authors: BW
authors: Day
authors: Angus
authors: A
authors: Harding
authors: Sergei
authors: S
authors: Kozlov
authors: Amanda W
authors: AW
authors: Kijas
authors: Kathleen S
authors: KS
authors: Ensbey
authors: David G
authors: DG
authors: Walker
authors: Martin F
authors: MF
authors: Lavin
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004261:DNA Replication; D005910:Glioma / Q000473:pathology*; D059765:Homologous Recombination; D006801:Humans; D014411:Neoplastic Stem Cells / Q000528:radiation effects*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011836:Radiation Tolerance; D059807:S Phase Cell Cycle Checkpoints; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins