Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage

• DOI: 10.1073/pnas.1405739111
• Publication Date: 2014-06-10T07:46:19Z
• Authors: Mark T. Gregory; Ga Young Park; Timothy C. Johnstone; Young-Sam Lee; Wei Yang; Stephen J. Lippard
• Keywords: 0301 basic medicine; Organoplatinum Compounds; Drug Resistance; Antineoplastic Agents; DNA-Directed DNA Polymerase; Crystallography, X-Ray; Cell Line; Structure-Activity Relationship; 03 medical and health sciences; monofunctional platinum drug candidates; Cell Line, Tumor; Neoplasms; Genetics; Humans; Cancer; X-ray crystallography; pol eta; Tumor; Crystallography; DNA; DNA, Neoplasm; Neoplasm Proteins; Phenanthridines; 3. Good health; 5.1 Pharmaceuticals; Drug Resistance, Neoplasm; X-Ray; Neoplasm; cancer therapy; Development of treatments and therapeutic interventions; DNA Damage

Significance In this work we investigated the ability of phenanthriplatin, a novel, potent monofunctional platinum anticancer agent, to inhibit DNA replication. Biochemical assays using site-specifically platinated DNA probes revealed the ability of phenanthriplatin lesions to block DNA replication by all polymerases tested except for Pol η, which exhibited inefficient but high-fidelity lesion bypass. Crystallographic studies of Pol η stalled at different stages of translesion synthesis past phenanthriplatin-platinated DNA provided insight into the mechanism by which the lesion inhibits DNA polymerases to induce cellular toxicity. Cytotoxicity studies using cells derived from patients who do not express functional Pol η suggest that phenanthriplatin-based therapy will be useful to treat cancers resistant to cisplatin by upregulating Pol η expression.