Publication

Back to overview

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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Davey Gabriela E., Adhireksan Zenita, Ma Zhujun, Riedel Tina, Sharma Deepti, Padavattan Sivaraman, Rhodes Daniela, Ludwig Alexander, Sandin Sara, Murray Benjamin S., Dyson Paul J., Davey Curt A.,
Project Modulation of the site specificity of binding of metal-based drugs to chromatin
Show all

Original article (peer-reviewed)

Journal Nature Communications
Volume (Issue) 8(1)
Page(s) 1575 - 1575
Title of proceedings Nature Communications
DOI 10.1038/s41467-017-01680-4

Open Access

URL http://doi.org/10.1038/s41467-017-01680-4
Type of Open Access Publisher (Gold Open Access)

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.
-