NUP98-p65 complex regulates DNA repair to maintain glioblastoma stem cells

FASEB J. 2025 Feb 28;39(4):e70401. doi: 10.1096/fj.202403256R.

Abstract

The nuclear pore complex (NPC) is an evolutionarily conserved structure that maintains the traffic between the nucleus and cytoplasm. Here, we profiled the expression of nucleoporins (NUPs) in glioblastoma stem cells (GSCs) and found that NUP98 promoted GSC maintenance and therapeutic resistance. GSCs preferentially expressed NUP98, which is essential for GSC tumorigenesis in vitro and in vivo. RNA sequencing demonstrated that NUP98 regulated the expression of key DNA damage and repair pathways. NUP98 formed a complex with transcription factor p65 to directly activate genes involved in homologous repair. Attenuation of NUP98 or p65 expression induced unrepaired intrinsic DNA damage and sensitized GSC to ionizing radiation. Clinically, overexpression of NUP98 informs poor clinical outcome among glioblastoma (GBM) patients. Collectively, our results demonstrate that NUP98-p65 represents a novel node in the regulation of DNA repair, suggesting a therapeutic strategy with potential clinical benefits for GBM patients.

Keywords: DNA damage and repair; NUP98; glioblastoma; glioblastoma stem cells; nuclear pore complex.

MeSH terms

  • Animals
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair*
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Mice
  • Neoplastic Stem Cells* / metabolism
  • Neoplastic Stem Cells* / pathology
  • Nuclear Pore Complex Proteins* / genetics
  • Nuclear Pore Complex Proteins* / metabolism

Substances

  • Nuclear Pore Complex Proteins
  • Nup98 protein, human