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J Biol Chem, Vol. 275, Issue 2, 1391-1397, January 14, 2000
From the 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 on
in 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.
Adozelesin Triggers DNA Damage Response Pathways and Arrests SV40
DNA Replication through Replication Protein A Inactivation*
§,§,
Department of Microbiology and
the Center for Microbial Pathogenesis, State University of New York
School of Medicine and Biomedical Sciences, Buffalo, New York 14214 and the ¶ Department of Pharmacology and Therapeutics, Roswell
Park Cancer Institute, Buffalo, New York 14263
*
This work was supported by American Cancer Society Grant GMC
87550 (to T. M.) and National Institutes of Health Grant GM 56406 (to
T. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Microbiology, School of Medicine & Biomedical Sciences, 138 Farber
Hall, State University of New York, Buffalo, NY 14214-3000. Tel.:
716-829-3381; Fax: 716-829-2158; E-mail: tmelendy@buffalo.edu.
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