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

Author

Listed:
  • Elisabeth Anne Adanma Obara

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Diana Aguilar-Morante

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Rikke Darling Rasmussen

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Alex Frias

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Kristoffer Vitting-Serup

    (Brain Tumor Biology, Danish Cancer Society Research Center
    University of Copenhagen
    University of Copenhagen)

  • Yi Chieh Lim

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Kirstine Juul Elbæk

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Henriette Pedersen

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Lina Vardouli

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Kamilla Ellermann Jensen

    (Brain Tumor Biology, Danish Cancer Society Research Center)

  • Jane Skjoth-Rasmussen

    (Copenhagen University Hospital)

  • Jannick Brennum

    (Copenhagen University Hospital)

  • Lucie Tuckova

    (Palacky University
    University Hospital Olomouc)

  • Robert Strauss

    (Genome Integrity Unit, Danish Cancer Society Research Center)

  • Christoffel Dinant

    (Genome Integrity Unit, Danish Cancer Society Research Center)

  • Jiri Bartek

    (Genome Integrity Unit, Danish Cancer Society Research Center
    Karolinska Institute)

  • Petra Hamerlik

    (Brain Tumor Biology, Danish Cancer Society Research Center
    Copenhagen University)

Abstract

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.

Suggested Citation

  • 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 & Kamill, 2020. "SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18549-8
    DOI: 10.1038/s41467-020-18549-8
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