Journal
GLIA
Volume 55, Issue 14, Pages 1416-1425Publisher
WILEY
DOI: 10.1002/glia.20556
Keywords
DNA repair; astrocytes; astrocytoma; apoptosis; mitochondria
Categories
Funding
- NCI NIH HHS [CA100045, R01 CA100045] Funding Source: Medline
- NIA NIH HHS [AG19602, R01 AG019602] Funding Source: Medline
- NIEHS NIH HHS [R01 ES003456, ES03456, R01 ES005865, R01 ES005865-15, ES05865, F32 ES005865] Funding Source: Medline
- NINDS NIH HHS [R01 NS047208-04, NS047208, R01 NS047208] Funding Source: Medline
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Primary astrocyte cultures were used to investigate the modulation of DNA repair as a tool for sensitizing astrocytes to genotoxic agents. Base excision repair (BER) is the principal mechanism by which mammalian cells repair alkylation damage to DNA and involves the processing of relatively nontoxic DNA adducts through a series of cytotoxic intermediates during the course of restoring normal DNA integrity. An adenoviral expression system was employed to target high levels of the BER pathway initiator, N-methylpurine glycosylase (MPG), to either the mitochondria or nucleus of primary astrocytes to test the hypothesis that an alteration in BER results in increased alkylation sensitivity. Increasing MPG activity significantly increased BER kinetics in both the mitochondria and nuclei. Although modulating MPG activity in mitochondria appeared to have little effect on alkylation sensitivity, increased nuclear MPG activity resulted in cell death in astrocyte cultures treated with methylnitrosourea (MNU). Caspase-3 cleavage was not detected, thus indicating that these alkylation sensitive astrocytes do not undergo a typical programmed cell death in response to MNU. Astrocytes were found to express relatively high levels of antiapoptotic Bcl-2 and Bcl-XL and very low levels of proapoptotic Bad and Bid suggesting that the mitochondrial pathway of apoptosis may be blocked making astrocytes less vulnerable to proapoptotic stimuli compared with other cell types. Consequently, this unique characteristic of astrocytes may be responsible, in part, for resistance of astrocytomas to chemotherapeutic agents. (C) 2007 Wiley-Liss, Inc.
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