BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery.
Glioblastoma multiforme (GBM) is an aggressive brain tumor that is resistant to all known therapies. Within these tumors, a CD133-positive cancer-initiating neural stem cell (NSC) population was shown to be resistant to gamma radiation through preferential activation of the DNA double-strand break (DSB) response machinery, including the ataxia-telangiectasia-mutated (ATM) kinase. ... The polycomb group protein BMI1 is enriched in CD133-positive GBM cells and required for their self-renewal in an INK4A/ARF-independent manner through transcriptional repression of alternate tumor suppressor pathways. We report here that BMI1 copurifies with DNA DSB response and nonhomologous end joining (NHEJ) repair proteins in GBM cells. BMI1 was enriched at the chromatin after irradiation and colocalized and copurified with ATM and the histone gammaH2AX. BMI1 also preferentially copurified with NHEJ proteins DNA-PK, PARP-1, hnRNP U, and histone H1 in CD133-positive GBM cells. BMI1 deficiency in GBM cells severely impaired DNA DSB response, resulting in increased sensitivity to radiation. In turn, BMI1 overexpression in normal NSCs enhanced ATM recruitment to the chromatin, the rate of gammaH2AX foci resolution, and resistance to radiation. BMI1 thus displays a previously uncharacterized function in controlling DNA DSB response and repair. Pharmacological inhibition of BMI1 combined with radiation therapy may provide an effective mean to target GBM stem cells.
Mesh Terms:
Antigens, CD, Brain Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, Chromatography, Liquid, Comet Assay, DNA Breaks, Double-Stranded, DNA Damage, DNA-Binding Proteins, Embryonic Stem Cells, Fetus, Flow Cytometry, Glioblastoma, Glycoproteins, Green Fluorescent Proteins, Humans, Immunoprecipitation, Neoplastic Stem Cells, Nuclear Proteins, Peptides, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Radiation Tolerance, Reactive Oxygen Species, Repressor Proteins, Tandem Mass Spectrometry, Transfection
Antigens, CD, Brain Neoplasms, Cell Line, Tumor, Cell Transformation, Neoplastic, Chromatography, Liquid, Comet Assay, DNA Breaks, Double-Stranded, DNA Damage, DNA-Binding Proteins, Embryonic Stem Cells, Fetus, Flow Cytometry, Glioblastoma, Glycoproteins, Green Fluorescent Proteins, Humans, Immunoprecipitation, Neoplastic Stem Cells, Nuclear Proteins, Peptides, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Radiation Tolerance, Reactive Oxygen Species, Repressor Proteins, Tandem Mass Spectrometry, Transfection
J. Neurosci.
Date: Jul. 28, 2010
PubMed ID: 20668194
View in: Pubmed Google Scholar
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