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Targeted inhibition of Replication Protein A reveals cytotoxic activity, synergy with chemotherapeutic DNA-damaging agents, and insight into cellular function.

ABSTRACT: Targeting uncontrolled cell proliferation and resistance to DNA-damaging chemotherapeutics with a single agent has significant potential in cancer treatment. Replication protein A (RPA), the eukaryotic ssDNA-binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. We have identified a novel small molecule that inhibits the in vitro and cellular ssDNA-binding activity of RPA, prevents cell cycle progression, induces cytotoxicity, and increases the efficacy of chemotherapeutic DNA-damaging agents. These results provide new insight into the mechanism of RPA-ssDNA interactions in chromosome maintenance and stability. This represents the first molecularly targeted eukaryotic DNA-binding inhibitor and reveals the utility of targeting a protein-DNA interaction as a therapeutic strategy for cancer treatment.

SUBMITTER: Shuck SC

PROVIDER: S-EPMC2882864 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Targeted inhibition of Replication Protein A reveals cytotoxic activity, synergy with chemotherapeutic DNA-damaging agents, and insight into cellular function.

Shuck Sarah C SC Turchi John J JJ

Cancer research 20100401 8

Targeting uncontrolled cell proliferation and resistance to DNA-damaging chemotherapeutics with a single agent has significant potential in cancer treatment. Replication protein A (RPA), the eukaryotic ssDNA-binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. We have identified a novel small molecule that inhibits the in vitro and cellular ssDNA-binding activity of RPA, prevents cell cycle progression, induces cytotoxicity, and increa ...[more]

PMID: 20395205

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