Adozelesin Triggers DNA Damage Response Pathways and Arrests SV40 DNA Replication through Replication Protein A Inactivation

The cyclopropylpyrroloindole anti-cancer drug, adozelesin, binds to and alkylates DNA. Treatment of human cells with low levels of adozelesin results in potent inhibition of both cellular and simian virus 40 (SV40) DNA replication. Extracts were prepared from adozelesin-treated cells and shown to be...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-01, Vol.275 (2), p.1391-1397
Main Authors: Liu, Jen-Sing, Kuo, Shu-Ru, McHugh, Mary M., Beerman, Terry A., Melendy, Thomas
Format: Article
Language:English
Subjects:
Adozelesin
Antineoplastic Agents, Alkylating - pharmacology
Aphidicolin - pharmacology
Benzofurans
Cell Line, Transformed
Cyclohexanecarboxylic Acids - pharmacology
Cyclohexenes
DNA Replication - drug effects
DNA-Binding Proteins - metabolism
Duocarmycins
Humans
Indoles
Kinetics
Phosphorylation
Replication Protein A
S Phase
Simian virus 40
Simian virus 40 - drug effects
Simian virus 40 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:The cyclopropylpyrroloindole anti-cancer drug, adozelesin, binds to and alkylates DNA. Treatment of human cells with low levels of adozelesin results in potent inhibition of both cellular and simian virus 40 (SV40) DNA replication. Extracts were prepared from adozelesin-treated cells and shown to be deficient in their ability to support SV40 DNA replication in vitro. This effect onin vitro DNA replication was dependent on both the concentration of adozelesin used and the time of treatment but was not due to the presence of adozelesin in the in vitro assay. Adozelesin treatment of cells was shown to result in the following: induction of p53 protein levels, hyperphosphorylation of replication protein A (RPA), and disruption of the p53-RPA complex (but not disruption of the RPA-cdc2 complex), indicating that adozelesin treatment triggers cellular DNA damage response pathways. Interestingly, in vitro DNA replication could be rescued in extracts from adozelesin-treated cells by the addition of exogenous RPA. Therefore, whereas adozelesin and other anti-cancer therapeutics trigger common DNA damage response markers, adozelesin causes DNA replication arrest through a unique mechanism. The S phase checkpoint response triggered by adozelesin acts by inactivating RPA in some function essential for SV40 DNA replication.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.275.2.1391