53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma.
The DNA damage response (DDR) plays a crucial role in tumor development in different tissues. Here, we show that p53-binding protein 1 (53BP1), a key element of the DDR, is heterozygously lost in approximately 20% of human glioblastoma multiforme (GBM) specimens, primarily of the Proneural subtype, and low 53BP1 expression levels are associated with worse prognosis. We present evidence that 53BP1 behaves as haploinsufficient tumor suppressor in a mouse model of platelet-derived growth factor-induced gliomagenesis. We also show that very low level of 53BP1 as found in 53BP1 null gliomas or robust 53BP1 gene silencing in glioma cell lines (but not 53BP1 heterozygous tumors or partial gene knockdown) sensitizes glioma cells to ionizing radiation (IR), both in vitro and in vivo. We further show the 53BP1 gene silencing induces defects in the nonhomologous end-joining (NHEJ) DNA repair pathway. These deficiencies lead to a failure to fully repair the damaged DNA upon exposure of glioma cells to IR with a consequent prolonged cell-cycle arrest and increased apoptosis. Our data suggest that either 53BP1 or other NHEJ components may be critical molecules to be pharmacologically targeted in GBM in combination with standard therapies.
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. hollande@mskcc.org
Massimo
M
Squatrito
Fabio
F
Vanoli
Nikolaus
N
Schultz
Maria
M
Jasin
Eric C
EC
Holland
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D002453:Cell Cycle; D002470:Cell Survival / Q000528:radiation effects*; D059766:DNA End-Joining Repair; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005910:Glioma / Q000473:pathology* / Q000532:radiotherapy; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D000071857:Tumor Suppressor p53-Binding Protein 1
D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1