Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage
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-diamminephenanthridinec...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2015
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| Online Access: | http://hdl.handle.net/1721.1/92784 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1826215926699130880 |
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| author | Gregory, Mark T. Park, Ga Young Johnstone, Timothy Lee, Young-Sam Yang, Wei Lippard, Stephen J. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Gregory, Mark T. Park, Ga Young Johnstone, Timothy Lee, Young-Sam Yang, Wei Lippard, Stephen J. |
| author_sort | Gregory, Mark T. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:39:14Z |
| format | Article |
| id | mit-1721.1/92784 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:39:14Z |
| publishDate | 2015 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/927842022-10-03T07:25:36Z Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage Gregory, Mark T. Park, Ga Young Johnstone, Timothy Lee, Young-Sam Yang, Wei Lippard, Stephen J. Massachusetts Institute of Technology. Department of Chemistry Park, Ga Young Johnstone, Timothy Lippard, Stephen J. 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. National Cancer Institute (U.S.) (Grant CA034992) 2015-01-12T16:03:26Z 2015-01-12T16:03:26Z 2014-06 2014-05 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/92784 Gregory, Mark T., Ga Young Park, Timothy C. Johnstone, Young-Sam Lee, Wei Yang, and Stephen J. Lippard. “Structural and Mechanistic Studies of Polymerase η Bypass of Phenanthriplatin DNA Damage.” Proceedings of the National Academy of Sciences 111, no. 25 (June 9, 2014): 9133–9138. https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1073/pnas.1405739111 Proceedings of the National Academy of Sciences of the United States of America Article 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. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Gregory, Mark T. Park, Ga Young Johnstone, Timothy Lee, Young-Sam Yang, Wei Lippard, Stephen J. Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage |
| title | Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage |
| title_full | Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage |
| title_fullStr | Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage |
| title_full_unstemmed | Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage |
| title_short | Structural and mechanistic studies of polymerase η bypass of phenanthriplatin DNA damage |
| title_sort | structural and mechanistic studies of polymerase η bypass of phenanthriplatin dna damage |
| url | http://hdl.handle.net/1721.1/92784 https://orcid.org/0000-0002-2693-4982 |
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