Abstract
DNA repair gene defects are found in virtually all human glioblastomas, but the genetic evidence for a direct role remains lacking. Here we demonstrate that combined inactivation of the XRCC4 non-homologous end-joining (NHEJ) DNA repair gene and p53 efficiently induces brain tumours with hallmark characteristics of human proneural/classical glioblastoma. The murine tumours exhibit PTEN loss of function instigated by reduced PTEN mRNA, and increased phosphorylated inactivation and stability as a consequence of aberrantly elevated CK2 provoked by p53 ablation and irrevocably deregulated by NHEJ inactivation. This results in DNA damage-resistant cytoplasmic PTEN and CK2 expression, and the attenuation of DNA repair genes. CK2 inhibition restores PTEN nuclear distribution and DNA repair activities and impairs tumour but not normal cell survival. These observations demonstrate that NHEJ contributes to p53-mediated glioblastoma suppression, and reveal a crucial role for PTEN in the early DNA damage signalling cascade, the inhibition of which promotes tumorigenicity and drug-resistant survival.
Highlights
DNA repair gene defects are found in virtually all human glioblastomas, but the genetic evidence for a direct role remains lacking
We develop a murine Glioblastoma multiforme (GBM) model in which knockout of both p53 and XRCC4 is targeted in neural stem/progenitors in the developing brain, and use this model to investigate the impact of non-homologous end-joining (NHEJ) deficiency on p53-mediated gliomagenesis
To investigate the relevance of NHEJ gene defects in human GBMs, we assessed the data from human GBM samples in the COSMIC17 and cBioPortal database[14] for molecular alterations in NHEJ genes
Summary
DNA repair gene defects are found in virtually all human glioblastomas, but the genetic evidence for a direct role remains lacking. Quantitative reverse transcription polymerase chain reaction (qRT–PCR) analysis revealed PTEN mRNA is significantly reduced and PI3K/AKT pathway genes are correspondingly activated in all 17 GXP GBMs (Fig. 2a and Supplementary Fig. 2a).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
