title: Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival.
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.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02143, USA.
authors.forename: Youn-Jung
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Balter
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02143, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Haas
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Sharma
authors.affiliation: Dana-Farber/Harvard Cancer Center Rodent Histopathology Core, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02143, USA.
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Yan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C511788:XRCC4 protein, mouse; D047390:Casein Kinase II; D051059:PTEN Phosphohydrolase