Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

被引:145
作者
Bartkova, J. [1 ,2 ]
Hamerlik, P. [1 ,2 ,3 ]
Stockhausen, M-T [4 ]
Ehrmann, J.
Hlobilkova, A.
Laursen, H. [5 ]
Kalita, O. [6 ]
Kolar, Z.
Poulsen, H. S. [4 ]
Broholm, H. [5 ]
Lukas, J. [1 ,2 ]
Bartek, J. [1 ,2 ,3 ]
机构
[1] Danish Canc Soc, Inst Canc Biol, DK-2100 Copenhagen, Denmark
[2] Danish Canc Soc, Ctr Genotox Stress Res, DK-2100 Copenhagen, Denmark
[3] Palacky Univ, Inst Mol & Translat Med, Lab Genome Integr, CR-77147 Olomouc, Czech Republic
[4] Copenhagen Univ Hosp, Dept Radiat Biol, Copenhagen, Denmark
[5] Copenhagen Univ Hosp, Dept Neuropathol, Copenhagen, Denmark
[6] Univ Hosp, Dept Neurosurg, Olomouc, Czech Republic
基金
新加坡国家研究基金会;
关键词
glioblastoma multiforme; DNA replication stress; oxidative DNA lesions; DNA damage checkpoints; p53; aberrations; ONCOGENE-INDUCED SENESCENCE; CANCER; REPAIR; CHECKPOINT; 53BP1; RADIORESISTANCE; PATHWAYS; BARRIER; BIOLOGY;
D O I
10.1038/onc.2010.249
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low-and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gamma H2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high-or low-oxygen culture conditions and in clinical specimens of both low-and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development. Oncogene (2010) 29, 5095-5102; doi:10.1038/onc.2010.249; published online 28 June 2010
引用
收藏
页码:5095 / 5102
页数:8
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