Targeting the OB-Folds of Replication Protein A with Small Molecules
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 characteriza...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2010-01-01
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| Series: | Journal of Nucleic Acids |
| Online Access: | http://dx.doi.org/10.4061/2010/304035 |
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| author | Victor J. Anciano Granadillo Jennifer N. Earley Sarah C. Shuck Millie M. Georgiadis Richard W. Fitch John J. Turchi |
| author_facet | Victor J. Anciano Granadillo Jennifer N. Earley Sarah C. Shuck Millie M. Georgiadis Richard W. Fitch John J. Turchi |
| author_sort | Victor J. Anciano Granadillo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-105fba2e831342b5a65de6130732dac8 |
| institution | OA Journals |
| issn | 2090-021X |
| language | English |
| publishDate | 2010-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Nucleic Acids |
| spelling | doaj-art-105fba2e831342b5a65de6130732dac82025-08-20T02:02:19ZengWileyJournal of Nucleic Acids2090-021X2010-01-01201010.4061/2010/304035304035Targeting the OB-Folds of Replication Protein A with Small MoleculesVictor J. Anciano Granadillo0Jennifer N. Earley1Sarah C. Shuck2Millie M. Georgiadis3Richard W. Fitch4John J. Turchi5Department of Medicine/Hematology and Oncology, Indiana University School of Medicine, Joseph E. Walther Hall, R3-C562, 980 W. Walnut Street, Indianapolis, IN 46202, USADepartment of Medicine/Hematology and Oncology, Indiana University School of Medicine, Joseph E. Walther Hall, R3-C562, 980 W. Walnut Street, Indianapolis, IN 46202, USADepartment of Medicine/Hematology and Oncology, Indiana University School of Medicine, Joseph E. Walther Hall, R3-C562, 980 W. Walnut Street, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Joseph E. Walther Hall, R3-C562, 980 W. Walnut Street, Indianapolis, IN 46202, USADepartment of Chemistry and Physics, Indiana State University, Terre Haute, IN 47809, USADepartment of Medicine/Hematology and Oncology, Indiana University School of Medicine, Joseph E. Walther Hall, R3-C562, 980 W. Walnut Street, Indianapolis, IN 46202, USAReplication 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.http://dx.doi.org/10.4061/2010/304035 |
| spellingShingle | Victor J. Anciano Granadillo Jennifer N. Earley Sarah C. Shuck Millie M. Georgiadis Richard W. Fitch John J. Turchi Targeting the OB-Folds of Replication Protein A with Small Molecules Journal of Nucleic Acids |
| title | Targeting the OB-Folds of Replication Protein A with Small Molecules |
| title_full | Targeting the OB-Folds of Replication Protein A with Small Molecules |
| title_fullStr | Targeting the OB-Folds of Replication Protein A with Small Molecules |
| title_full_unstemmed | Targeting the OB-Folds of Replication Protein A with Small Molecules |
| title_short | Targeting the OB-Folds of Replication Protein A with Small Molecules |
| title_sort | targeting the ob folds of replication protein a with small molecules |
| url | http://dx.doi.org/10.4061/2010/304035 |
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