Targeted inhibition of Replication Protein A reveals cytotoxic activity, synergy with chemotherapeutic DNA-damaging agents, and insight into cellular function.
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.
Shuck
Sarah C
SC
Departments of Medicine and Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Turchi
John J
JJ
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy*; D051716:Replication Protein A / Q000378:metabolism*
D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D051716:Replication Protein A
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