L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1

Lin Cheng, Qiulian Wu, Zhi Huang, Olga A. Guryanova, Qian Huang, Weinian Shou, Jeremy N. Rich, Shideng Bao

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

Glioblastomas (GBMs) are highly lethal brain tumours with current therapies limited to palliation due to therapeutic resistance. We previously demonstrated that GBM stem cells (GSCs) display a preferential activation of DNA damage checkpoint and are relatively resistant to radiation. However, the molecular mechanisms underlying the preferential checkpoint response in GSCs remain undefined. Here, we show that L1CAM (CD171) regulates DNA damage checkpoint responses and radiosensitivity of GSCs through nuclear translocation of L1CAM intracellular domain (L1-ICD). Targeting L1CAM by RNA interference attenuated DNA damage checkpoint activation and repair, and sensitized GSCs to radiation. L1CAM regulates expression of NBS1, a critical component of the MRE11-RAD50-NBS1 (MRN) complex that activates ataxia telangiectasia mutated (ATM) kinase and early checkpoint response. Ectopic expression of NBS1 in GSCs rescued the decreased checkpoint activation and radioresistance caused by L1CAM knockdown, demonstrating that L1CAM signals through NBS1 to regulate DNA damage checkpoint responses. Mechanistically, nuclear translocation of L1-ICD mediates NBS1 upregulation via c-Myc. These data demonstrate that L1CAM augments DNA damage checkpoint activation and radioresistance of GSCs through L1-ICD-mediated NBS1 upregulation and the enhanced MRN-ATM-Chk2 signalling.

Original languageEnglish (US)
Pages (from-to)800-813
Number of pages14
JournalEMBO Journal
Volume30
Issue number5
DOIs
StatePublished - Mar 2 2011

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Keywords

  • DNA damage checkpoint
  • glioblastoma stem cells
  • L1CAM
  • NBS1
  • radioresistance

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Cheng, L., Wu, Q., Huang, Z., Guryanova, O. A., Huang, Q., Shou, W., Rich, J. N., & Bao, S. (2011). L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1. EMBO Journal, 30(5), 800-813. https://doi.org/10.1038/emboj.2011.10