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

Gabriela E. Davey, Zenita Adhireksan, Zhujun Ma, Tina Riedel, Deepti Sharma, Sivaraman Padavattan, Daniela Rhodes, Alexander Ludwig, Sara Sandin, Benjamin S. Murray (), Paul J. Dyson () and Curt A. Davey ()
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Gabriela E. Davey: Nanyang Technological University
Zenita Adhireksan: Nanyang Technological University
Zhujun Ma: Nanyang Technological University
Tina Riedel: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Deepti Sharma: Nanyang Technological University
Sivaraman Padavattan: Nanyang Technological University
Daniela Rhodes: Nanyang Technological University
Alexander Ludwig: Nanyang Technological University
Sara Sandin: Nanyang Technological University
Benjamin S. Murray: University of Hull
Paul J. Dyson: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Curt A. Davey: Nanyang Technological University

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01680-4

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