title: Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage.
abstract: Platinum drugs are a mainstay of anticancer chemotherapy. Nevertheless, tumors often display inherent or acquired resistance to platinum-based treatments, prompting the search for new compounds that do not exhibit cross-resistance with current therapies. Phenanthriplatin, cis-diamminephenanthridinechloroplatinum(II), is a potent monofunctional platinum complex that displays a spectrum of activity distinct from those of the clinically approved platinum drugs. Inhibition of RNA polymerases by phenanthriplatin lesions has been implicated in its mechanism of action. The present study evaluates the ability of phenanthriplatin lesions to inhibit DNA replication, a function disrupted by traditional platinum drugs. Phenanthriplatin lesions effectively inhibit DNA polymerases ν, ζ, and κ and the Klenow fragment. In contrast to results obtained with DNA damaged by cisplatin, all of these polymerases were capable of inserting a base opposite a phenanthriplatin lesion, but only Pol η, an enzyme efficient in translesion synthesis, was able to fully bypass the adduct, albeit with low efficiency. X-ray structural characterization of Pol η complexed with site-specifically platinated DNA at both the insertion and +1 extension steps reveals that phenanthriplatin on DNA interacts with and inhibits Pol η in a manner distinct from that of cisplatin-DNA adducts. Unlike cisplatin and oxaliplatin, the efficacies of which are influenced by Pol η expression, phenanthriplatin is highly toxic to both Pol η+ and Pol η- cells. Given that increased expression of Pol η is a known mechanism by which cells resist cisplatin treatment, phenanthriplatin may be valuable in the treatment of cancers that are, or can easily become, resistant to cisplatin.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases andThe Johns Hopkins University-National Institutes of Health Graduate Partnership Program, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gregory
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Ga Young
authors.initials: GY
authors.lastname: Park
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Johnstone
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases and.
authors.forename: Young-Sam
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases and.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 lippard@mit.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D010617:Phenanthridines; C587603:phenanthriplatin; D004259:DNA-Directed DNA Polymerase; C546205:POLN protein, human
keywords: X-ray crystallography; cancer therapy; monofunctional platinum drug candidates; pol eta