Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation
The ‘acidic patch’ is a highly electronegative cleft on the histone H2A–H2B dimer in the nucleosome. It is a fundamental motif for protein binding and chromatin dynamics, but the cellular impact of targeting this potentially therapeutic site with exogenous molecules remains unclear. Here, we charact...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/89472 http://hdl.handle.net/10220/44965 |
| _version_ | 1826123506580979712 |
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| author | Davey, Gabriela Elzbieta Adhireksan, Zenita Ma, Zhujun Riedel, Tina Sharma, Deepti Padavattan, Sivaraman Rhodes, Daniela Ludwig, Alexander Sandin, Sara Murray, Benjamin S. Dyson, Paul J. Davey, Curtis Alexander |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Davey, Gabriela Elzbieta Adhireksan, Zenita Ma, Zhujun Riedel, Tina Sharma, Deepti Padavattan, Sivaraman Rhodes, Daniela Ludwig, Alexander Sandin, Sara Murray, Benjamin S. Dyson, Paul J. Davey, Curtis Alexander |
| author_sort | Davey, Gabriela Elzbieta |
| collection | NTU |
| description | The ‘acidic patch’ is a highly electronegative cleft on the histone H2A–H2B dimer in the nucleosome. It is a fundamental motif for protein binding and chromatin dynamics, but the cellular impact of targeting this potentially therapeutic site with exogenous molecules remains unclear. Here, we characterize a family of binuclear ruthenium compounds that selectively target the nucleosome acidic patch, generating intra-nucleosomal H2A-H2B cross-links as well as inter-nucleosomal cross-links. In contrast to cisplatin or the progenitor RAPTA-C anticancer drugs, the binuclear agents neither arrest specific cell cycle phases nor elicit DNA damage response, but rather induce an irreversible, anomalous state of condensed chromatin that ultimately results in apoptosis. In vitro, the compounds induce misfolding of chromatin fibre and block the binding of the regulator of chromatin condensation 1 (RCC1) acidic patch-binding protein. This family of chromatin-modifying molecules has potential for applications in drug development and as tools for chromatin research. |
| first_indexed | 2024-10-01T06:05:46Z |
| format | Journal Article |
| id | ntu-10356/89472 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:05:46Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/894722023-02-28T17:03:49Z Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation Davey, Gabriela Elzbieta Adhireksan, Zenita Ma, Zhujun Riedel, Tina Sharma, Deepti Padavattan, Sivaraman Rhodes, Daniela Ludwig, Alexander Sandin, Sara Murray, Benjamin S. Dyson, Paul J. Davey, Curtis Alexander Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences NTU Institute of Structural Biology Ruthenium Chromatin Condensation The ‘acidic patch’ is a highly electronegative cleft on the histone H2A–H2B dimer in the nucleosome. It is a fundamental motif for protein binding and chromatin dynamics, but the cellular impact of targeting this potentially therapeutic site with exogenous molecules remains unclear. Here, we characterize a family of binuclear ruthenium compounds that selectively target the nucleosome acidic patch, generating intra-nucleosomal H2A-H2B cross-links as well as inter-nucleosomal cross-links. In contrast to cisplatin or the progenitor RAPTA-C anticancer drugs, the binuclear agents neither arrest specific cell cycle phases nor elicit DNA damage response, but rather induce an irreversible, anomalous state of condensed chromatin that ultimately results in apoptosis. In vitro, the compounds induce misfolding of chromatin fibre and block the binding of the regulator of chromatin condensation 1 (RCC1) acidic patch-binding protein. This family of chromatin-modifying molecules has potential for applications in drug development and as tools for chromatin research. MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) Published version 2018-06-06T03:37:31Z 2019-12-06T17:26:16Z 2018-06-06T03:37:31Z 2019-12-06T17:26:16Z 2017 Journal Article Davey, G. E., Adhireksan, Z., Ma, Z., Riedel, T., Sharma, D., Padavattan, S., et al. (2017). Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation. Nature Communications, 8(1), 1575-. 2041-1723 https://hdl.handle.net/10356/89472 http://hdl.handle.net/10220/44965 10.1038/s41467-017-01680-4 en Nature Communications © 2017 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 13 p. application/pdf |
| spellingShingle | Ruthenium Chromatin Condensation Davey, Gabriela Elzbieta Adhireksan, Zenita Ma, Zhujun Riedel, Tina Sharma, Deepti Padavattan, Sivaraman Rhodes, Daniela Ludwig, Alexander Sandin, Sara Murray, Benjamin S. Dyson, Paul J. Davey, Curtis Alexander Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation |
| title | Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation |
| title_full | Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation |
| title_fullStr | Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation |
| title_full_unstemmed | Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation |
| title_short | Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation |
| title_sort | nucleosome acidic patch targeting binuclear ruthenium compounds induce aberrant chromatin condensation |
| topic | Ruthenium Chromatin Condensation |
| url | https://hdl.handle.net/10356/89472 http://hdl.handle.net/10220/44965 |
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