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SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells

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  • Elisabeth Anne Adanma Obara
  • Diana Aguilar-Morante
  • Rikke Darling Rasmussen
  • Alex Frias
  • Kristoffer Vitting-Serup
  • Yi Chieh Lim
  • Kirstine Juul Elbæk
  • Henriette Pedersen
  • Lina Vardouli
  • Kamilla Ellermann Jensen
  • Jane Skjoth-Rasmussen
  • Jannick Brennum
  • Lucie Tuckova
  • Robert Strauss
  • Christoffel Dinant
  • Jiri Bartek
  • Petra Hamerlik
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Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.

Original languageEnglish
Article number4709
JournalNature Communications
Volume11
Issue number1
Pages (from-to)4709
ISSN2041-1723
DOIs
Publication statusPublished - 18 Sep 2020

    Research areas

  • Animals, Apoptosis, BRCA1 Protein, Brain Neoplasms/genetics, Cell Cycle Checkpoints, Cell Line, Tumor, DNA Repair, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Gene Silencing, Genomic Instability, Glioblastoma/genetics, HEK293 Cells, Heterografts, Humans, Mice, Mice, Inbred BALB C, Neoplastic Stem Cells/pathology, RNA, Small Interfering/genetics, Radiation Tolerance, Radiation, Ionizing, Transcription Factors/genetics, Transcriptome

ID: 61348777