X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct
DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the w...
| Main Authors: | , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
National Academy of Sciences (U.S.)
2013
|
| Online Access: | http://hdl.handle.net/1721.1/82147 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1811092732861480960 |
|---|---|
| author | Zhu, Guangyu Lippard, Stephen J. Wang, Dong Huang, Xuhui |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Zhu, Guangyu Lippard, Stephen J. Wang, Dong Huang, Xuhui |
| author_sort | Zhu, Guangyu |
| collection | MIT |
| description | DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs. |
| first_indexed | 2024-09-23T15:24:00Z |
| format | Article |
| id | mit-1721.1/82147 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:24:00Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/821472022-10-02T02:33:28Z X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct Zhu, Guangyu Lippard, Stephen J. Wang, Dong Huang, Xuhui Massachusetts Institute of Technology. Department of Chemistry Zhu, Guangyu Lippard, Stephen J. DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs. National Cancer Institute (U.S.) (Grant CA034992) 2013-11-15T20:28:15Z 2013-11-15T20:28:15Z 2010-05 2010-03 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/82147 Wang, D., G. Zhu, X. Huang, and S. J. Lippard. “X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct.” Proceedings of the National Academy of Sciences 107, no. 21 (May 25, 2010): 9584-9589. https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1073/pnas.1002565107 Proceedings of the National Academy of Sciences 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 | Zhu, Guangyu Lippard, Stephen J. Wang, Dong Huang, Xuhui X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct |
| title | X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct |
| title_full | X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct |
| title_fullStr | X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct |
| title_full_unstemmed | X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct |
| title_short | X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct |
| title_sort | x ray structure and mechanism of rna polymerase ii stalled at an antineoplastic monofunctional platinum dna adduct |
| url | http://hdl.handle.net/1721.1/82147 https://orcid.org/0000-0002-2693-4982 |
| work_keys_str_mv | AT zhuguangyu xraystructureandmechanismofrnapolymeraseiistalledatanantineoplasticmonofunctionalplatinumdnaadduct AT lippardstephenj xraystructureandmechanismofrnapolymeraseiistalledatanantineoplasticmonofunctionalplatinumdnaadduct AT wangdong xraystructureandmechanismofrnapolymeraseiistalledatanantineoplasticmonofunctionalplatinumdnaadduct AT huangxuhui xraystructureandmechanismofrnapolymeraseiistalledatanantineoplasticmonofunctionalplatinumdnaadduct |