TY - JOUR
T1 - SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells
AU - Obara, Elisabeth Anne Adanma
AU - Aguilar-Morante, Diana
AU - Rasmussen, Rikke Darling
AU - Frias, Alex
AU - Vitting-Serup, Kristoffer
AU - Lim, Yi Chieh
AU - Elbæk, Kirstine Juul
AU - Pedersen, Henriette
AU - Vardouli, Lina
AU - Jensen, Kamilla Ellermann
AU - Skjoth-Rasmussen, Jane
AU - Brennum, Jannick
AU - Tuckova, Lucie
AU - Strauss, Robert
AU - Dinant, Christoffel
AU - Bartek, Jiri
AU - Hamerlik, Petra
PY - 2020/9/18
Y1 - 2020/9/18
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - BRCA1 Protein
KW - Brain Neoplasms/genetics
KW - Cell Cycle Checkpoints
KW - Cell Line, Tumor
KW - DNA Repair
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Gene Knockdown Techniques
KW - Gene Silencing
KW - Genomic Instability
KW - Glioblastoma/genetics
KW - HEK293 Cells
KW - Heterografts
KW - Humans
KW - Mice
KW - Mice, Inbred BALB C
KW - Neoplastic Stem Cells/pathology
KW - RNA, Small Interfering/genetics
KW - Radiation Tolerance
KW - Radiation, Ionizing
KW - Transcription Factors/genetics
KW - Transcriptome
UR - https://www.scopus.com/pages/publications/85091179549
U2 - 10.1038/s41467-020-18549-8
DO - 10.1038/s41467-020-18549-8
M3 - Journal article
C2 - 32948765
SN - 2041-1722
VL - 11
SP - 4709
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4709
ER -