BMI1 Confers Radioresistance to Normal and Cancerous Neural Stem Cells through Recruitment of the DNA Damage Response Machinery

Abstract

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 anINK4A/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 γH2AX. 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 γH2AX 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.

Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins

“…The presence of Ligase IV in Rd1;Bmi1 −/− retina suggests that the neuroprotective effect of Bmi1 deletion occurs downstream of DNA repair, via CDK inactivation. Nonetheless, we cannot exclude a modest effect of Bmi1 deletion on DNA repair, because Bmi1 has been reported to be involved in DNA repair initiation (37,38). In contrast, there is recent evidence that Bmi1 loss increases oxidative stress in neurons (39) as well as in other cell types (40).…”

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

“…Since tumorigenesis can be considered as aberrant organogenesis carried on by cancer SCs (CSCs), clarification of the relationship between tumors and the tissue SCs may have important implications for therapy [54]. Phenomena of radioresistance have been evidenced in highly malignant glioma and MB and have been ascribed to the presence in the tumor tissues of cells expressing the SC marker CD133 [55][56][57]. Because CSCs may use DNA repair mechanisms used by SCs to mediate chemoresistance and radioresistance [1], signaling pathways activated by NSCs in response to radiation may be exploited to increase the efficacy of therapies against brain tumors.…”

Neuronal stem cells in the central nervous system and in human diseases

“…The inhibition of Chk1 and Chk2 significantly increases GSC radio-sensitivity (Bao et al, 2006a). Further studies have illustrated that the knockdown of some other DNA repair-related genes, such as L1CAM, NBS-1, and Bim1, reduces GSC radioresistance (Facchino et al, 2010;Cheng et al, 2011), suggesting that hyper-active DNA repair pathways make radiotherapy less effective in the clinical treatment of gliomas.…”