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Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation

Davey, Gabriela E.; Dyson, Paul J.; Davey, Curt A.; Davey, Gabriela; Adhireksan, Zenita; Ma, Zhujun; Riedel, Tina; Sharma, Deepti; Padavattan, Sivaraman; Rhodes, Daniela; Ludwig, Alexander; Sandin, Sara; Murray, Benjamin S.; Dyson, Paul; Davey, Curt

Authors

Gabriela E. Davey

Paul J. Dyson

Curt A. Davey

Gabriela Davey

Zenita Adhireksan

Zhujun Ma

Tina Riedel

Deepti Sharma

Sivaraman Padavattan

Daniela Rhodes

Alexander Ludwig

Sara Sandin

Paul Dyson

Curt Davey



Abstract

© 2017 The Author(s). 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.

Citation

Davey, G. E., Dyson, P. J., Davey, C. A., Davey, G., Adhireksan, Z., Ma, Z., …Davey, C. (2017). Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation. Nature communications, 8(1), https://doi.org/10.1038/s41467-017-01680-4

Acceptance Date Oct 9, 2017
Online Publication Date Nov 17, 2017
Publication Date Dec 1, 2017
Deposit Date Nov 17, 2017
Publicly Available Date Nov 30, 2017
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
Article Number 1575
DOI https://doi.org/10.1038/s41467-017-01680-4
Keywords General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
Public URL https://hull-repository.worktribe.com/output/456552
Publisher URL https://www.nature.com/articles/s41467-017-01680-4
Copyright Statement © The Author(s) 2017

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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/

Copyright Statement
© The Author(s) 2017



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