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.