Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival

Youn-Jung Kang, Barbara Balter, Eva Csizmadia, Brian Haas, Himanshu Sharma, Roderick Bronson and Catherine T. Yan ()
Additional contact information
Youn-Jung Kang: Beth Israel Deaconess Medical Center
Barbara Balter: Beth Israel Deaconess Medical Center
Eva Csizmadia: Beth Israel Deaconess Medical Center
Brian Haas: The Broad Institute of MIT and Harvard
Himanshu Sharma: Beth Israel Deaconess Medical Center
Roderick Bronson: Dana-Farber/Harvard Cancer Center Rodent Histopathology Core, Harvard Medical School
Catherine T. Yan: Beth Israel Deaconess Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms14013 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14013

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms14013

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().