Effect of a monofunctional phenanthriplatin-DNA adduct on RNA polymerase II transcriptional fidelity and translesion synthesis.
Transcription inhibition by platinum anticancer drugs is an important component of their mechanism of action. Phenanthriplatin, a cisplatin derivative containing phenanthridine in place of one of the chloride ligands, forms highly potent monofunctional adducts on DNA having a structure and spectrum of anticancer activity distinct from those of the parent drug. Understanding the functional consequences of DNA damage by phenanthriplatin for the normal functions of RNA polymerase II (Pol II), the major cellular transcription machinery component, is an important step toward elucidating its mechanism of action. In this study, we present the first systematic mechanistic investigation that addresses how a site-specific phenanthriplatin-DNA d(G) monofunctional adduct affects the Pol II elongation and transcriptional fidelity checkpoint steps. Pol II processing of the phenanthriplatin lesion differs significantly from that of the canonical cisplatin-DNA 1,2-d(GpG) intrastrand cross-link. A majority of Pol II elongation complexes stall after successful addition of CTP opposite the phenanthriplatin-dG adduct in an error-free manner, with specificity for CTP incorporation being essentially the same as for undamaged dG on the template. A small portion of Pol II undergoes slow, error-prone bypass of the phenanthriplatin-dG lesion, which resembles DNA polymerases that similarly switch from high-fidelity replicative DNA processing (error-free) to low-fidelity translesion DNA synthesis (error-prone) at DNA damage sites. These results provide the first insights into how the Pol II transcription machinery processes the most abundant DNA lesion of the monofunctional phenanthriplatin anticancer drug candidate and enrich our general understanding of Pol II transcription fidelity maintenance, lesion bypass, and transcription-derived mutagenesis. Because of the current interest in monofunctional, DNA-damaging metallodrugs, these results are of likely relevance to a broad spectrum of next-generation anticancer agents being developed by the medicinal inorganic chemistry community.
Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of California, San Diego, La Jolla, California 92093, United States.
Matthew W
MW
Kellinger
Ga Young
GY
Park
Jenny
J
Chong
Stephen J
SJ
Lippard
Dong
D
Wang
D018736:DNA Adducts / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*
D018736:DNA Adducts; D009944:Organoplatinum Compounds; D010617:Phenanthridines; C587603:phenanthriplatin; D012319:RNA Polymerase II