Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA
HMGB1, one of the most abundant nuclear proteins, has a strong binding affinity for cisplatin-modified DNA. It has been proposed that HMGB1 enhances the anticancer efficacy of cisplatin by shielding platinated DNA lesions from repair. Two cysteine residues in HMGB1 domain A form a reversible disulfi...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society
2012
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| Online Access: | http://hdl.handle.net/1721.1/69874 https://orcid.org/0000-0002-2693-4982 |
| _version_ | 1811077204631617536 |
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| author | Park, SeMi Lippard, Stephen J. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Park, SeMi Lippard, Stephen J. |
| author_sort | Park, SeMi |
| collection | MIT |
| description | HMGB1, one of the most abundant nuclear proteins, has a strong binding affinity for cisplatin-modified DNA. It has been proposed that HMGB1 enhances the anticancer efficacy of cisplatin by shielding platinated DNA lesions from repair. Two cysteine residues in HMGB1 domain A form a reversible disulfide bond under mildly oxidizing conditions. The reduced domain A protein binds to a 25-bp DNA probe containing a central 1,2-d(GpG) intrastrand cross-link, the major platinum−DNA adduct, with a 10-fold greater binding affinity than the oxidized domain A. The binding affinities of singly and doubly mutated HMGB1 domain A, respectively deficient in one or both cysteine residues that form the disulfide bond, are unaffected by changes in external redox conditions. The redox-dependent nature of the binding of HMGB1 domain A to cisplatin-modified DNA suggests that formation of the intradomain disulfide bond induces a conformational change that disfavors binding to cisplatin-modified DNA. Hydroxyl radical footprinting analyses of wild-type domain A bound to platinated DNA under different redox conditions revealed identical cleavage patterns, implying that the asymmetric binding mode of the protein across from the platinated lesion is conserved irrespective of the redox state. The results of this study reveal that the cellular redox environment can influence the interaction of HMGB1 with the platinated DNA and suggest that the redox state of the A domain is a potential factor in regulating the role of the protein in modulating the activity of cisplatin as an anticancer drug. |
| first_indexed | 2024-09-23T10:39:27Z |
| format | Article |
| id | mit-1721.1/69874 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:39:27Z |
| publishDate | 2012 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | mit-1721.1/698742022-09-27T14:01:24Z Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA Park, SeMi Lippard, Stephen J. Massachusetts Institute of Technology. Department of Chemistry Lippard, Stephen J. Park, SeMi Lippard, Stephen J. HMGB1, one of the most abundant nuclear proteins, has a strong binding affinity for cisplatin-modified DNA. It has been proposed that HMGB1 enhances the anticancer efficacy of cisplatin by shielding platinated DNA lesions from repair. Two cysteine residues in HMGB1 domain A form a reversible disulfide bond under mildly oxidizing conditions. The reduced domain A protein binds to a 25-bp DNA probe containing a central 1,2-d(GpG) intrastrand cross-link, the major platinum−DNA adduct, with a 10-fold greater binding affinity than the oxidized domain A. The binding affinities of singly and doubly mutated HMGB1 domain A, respectively deficient in one or both cysteine residues that form the disulfide bond, are unaffected by changes in external redox conditions. The redox-dependent nature of the binding of HMGB1 domain A to cisplatin-modified DNA suggests that formation of the intradomain disulfide bond induces a conformational change that disfavors binding to cisplatin-modified DNA. Hydroxyl radical footprinting analyses of wild-type domain A bound to platinated DNA under different redox conditions revealed identical cleavage patterns, implying that the asymmetric binding mode of the protein across from the platinated lesion is conserved irrespective of the redox state. The results of this study reveal that the cellular redox environment can influence the interaction of HMGB1 with the platinated DNA and suggest that the redox state of the A domain is a potential factor in regulating the role of the protein in modulating the activity of cisplatin as an anticancer drug. National Cancer Institute (U.S.) (Grant CA034992) 2012-03-28T15:07:18Z 2012-03-28T15:07:18Z 2011-02 2011-01 Article http://purl.org/eprint/type/JournalArticle 0006-2960 1520-4995 http://hdl.handle.net/1721.1/69874 Park, Semi, and Stephen J. Lippard. “Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA.” Biochemistry 50.13 (2011): 2567–2574. https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1021/bi2000214 Biochemistry 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 American Chemical Society Prof. Lippard via Erja Kajosalo |
| spellingShingle | Park, SeMi Lippard, Stephen J. Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA |
| title | Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA |
| title_full | Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA |
| title_fullStr | Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA |
| title_full_unstemmed | Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA |
| title_short | Redox State-Dependent Interaction of HMGB1 and Cisplatin-Modified DNA |
| title_sort | redox state dependent interaction of hmgb1 and cisplatin modified dna |
| url | http://hdl.handle.net/1721.1/69874 https://orcid.org/0000-0002-2693-4982 |
| work_keys_str_mv | AT parksemi redoxstatedependentinteractionofhmgb1andcisplatinmodifieddna AT lippardstephenj redoxstatedependentinteractionofhmgb1andcisplatinmodifieddna |