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dc.contributor.authorKellinger, Matthew W.
dc.contributor.authorPark, Ga Young
dc.contributor.authorChong, Jenny
dc.contributor.authorLippard, Stephen J.
dc.contributor.authorWang, Dong
dc.date.accessioned2014-08-07T14:45:01Z
dc.date.available2014-08-07T14:45:01Z
dc.date.issued2013-08
dc.date.submitted2013-05
dc.identifier.issn0002-7863
dc.identifier.issn1520-5126
dc.identifier.urihttp://hdl.handle.net/1721.1/88576
dc.description.abstractTranscription 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.en_US
dc.description.sponsorshipNational Cancer Institute (U.S.)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (CA034992)en_US
dc.description.sponsorshipMisrock Foundation (Postdoctoral Fellowship)en_US
dc.language.isoen_US
dc.publisherAmerican Chemical Society (ACS)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1021/ja405475yen_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceProf. Lippard via Erja Kajosaloen_US
dc.titleEffect of a Monofunctional Phenanthriplatin-DNA Adduct on RNA Polymerase II Transcriptional Fidelity and Translesion Synthesisen_US
dc.typeArticleen_US
dc.identifier.citationKellinger, Matthew W., Ga Young Park, Jenny Chong, Stephen J. Lippard, and Dong Wang. “Effect of a Monofunctional Phenanthriplatin-DNA Adduct on RNA Polymerase II Transcriptional Fidelity and Translesion Synthesis.” Journal of the American Chemical Society 135, no. 35 (September 4, 2013): 13054–13061.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistryen_US
dc.contributor.approverLippard, Stephen J.en_US
dc.contributor.mitauthorPark, Ga Youngen_US
dc.contributor.mitauthorLippard, Stephen J.en_US
dc.relation.journalJournal of the American Chemical Societyen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsKellinger, Matthew W.; Park, Ga Young; Chong, Jenny; Lippard, Stephen J.; Wang, Dongen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-2693-4982
mit.licensePUBLISHER_POLICYen_US


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