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Departments of Microbiology and Biochemistry and the Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, SUNY, School of Medicine and Biomedical Sciences, Buffalo, New York 14214 [J-S. L., S-R. K., T. M.], and Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263 [T. A. B.]

Adozelesin is an alkylating minor groove DNA binder that is capable of rapidly inhibiting DNA replication in treated cells through a trans-acting mechanism and preferentially arrests cells in S phase. It has been shown previously that in cells treated with adozelesin, replication protein A (RPA) activity is deficient, and the middle subunit of RPA is hyperphosphorylated. The adozelesin-induced RPA hyperphosphorylation can be blocked by the replicative DNA polymerase inhibitor, aphidicolin, suggesting that adozelesin-triggered cellular DNA damage responses require active DNA replication forks. These data imply that cellular DNA damage responses to adozelesin treatment are preferentially induced in S phase. Here, we show that RPA hyperphosphorylation, RPA intranuclear focalization, and -H2AX intranuclear focalization induced by adozelesin treatment are all dependent on DNA replication fork progression, and focalization is only induced in S phase cells. These findings are similar to those seen with the S phase-specific DNA-damaging agent, camptothecin. Conversely, all three DNA damage responses are independent of either S phase or replication fork progression when induced by treatment with the DNA strand scission agent, C-1027. Furthermore, we demonstrate that adozelesin-induced RPA and -H2AX intranuclear foci appear to colocalize within the nuclei of S phase cells.

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