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Journal of Nucleic Acids
Volume 2010, Article ID 304035, 11 pages
http://dx.doi.org/10.4061/2010/304035
Research Article

Targeting the OB-Folds of Replication Protein A with Small Molecules

1Department of Medicine/Hematology and Oncology, Indiana University School of Medicine, Joseph E. Walther Hall, R3-C562, 980 W. Walnut Street, Indianapolis, IN 46202, USA
2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Joseph E. Walther Hall, R3-C562, 980 W. Walnut Street, Indianapolis, IN 46202, USA
3Department of Biochemistry, Vanderbilt University School of Medicine, 850 Robinson Research Building, Nashville, TN 37209, USA
4Department of Chemistry and Physics, Indiana State University, Terre Haute, IN 47809, USA

Received 19 August 2010; Accepted 27 September 2010

Academic Editor: Ashis Basu

Copyright © 2010 Victor J. Anciano Granadillo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Replication protein A (RPA) is the main eukaryotic single-strand (ss) DNA-binding protein involved in DNA replication and repair. We have identified and developed two classes of small molecule inhibitors (SMIs) that show in vitro inhibition of the RPA-DNA interaction. We present further characterization of these SMIs with respect to their target binding, mechanism of action, and specificity. Both reversible and irreversible modes of inhibition are observed for the different classes of SMIs with one class found to specifically interact with DNA-binding domains A and B (DBD-A/B) of RPA. In comparison with other oligonucleotide/oligosaccharide binding-fold (OB-fold) containing ssDNA-binding proteins, one class of SMIs displayed specificity for the RPA protein. Together these data demonstrate that the specific targeting of a protein-DNA interaction can be exploited towards interrogating the cellular activity of RPA as well as increasing the efficacy of DNA-damaging chemotherapeutics used in cancer treatment.