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

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 and Petra Hamerlik ()
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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
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
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
Petra Hamerlik: Brain Tumor Biology, Danish Cancer Society Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18549-8

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