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.
Highlights
The ‘acidic patch’ is a highly electronegative cleft on the histone H2A–H2B dimer in the nucleosome
We find that the binuclears are selective for the RU1/RU2 sites in the nucleosome acidic patch, generate substantial quantities of adducts in cellular chromatin but do not elicit a DNA damage response, and give rise to an unusual mode of cell killing associated with an irreversible state of aberrant chromatin condensation
The RAPTA-based binuclear agents characterized here display the striking ability to induce a catastrophic state of chromatin condensation, which persists for many hours and coincides with cell death
Summary
The ‘acidic patch’ is a highly electronegative cleft on the histone H2A–H2B dimer in the nucleosome. There are at least six distinct epigenetic features of chromatin that are modulated in a site-specific and cell state-dependent manner to achieve precise control of genomic activities, notably transcription These entail mostly attributes that relate to individual nucleosomes, including histone octamer occupancy/positioning on the double helix and an enormity of potential posttranslational modifications to the histone proteins, in addition to substitutions with different histone variants and methylation of the DNA2, 3. In cancer cells for instance, aberrant nucleosome occupancy, histone post-translational modifications and DNA methylation work in unison to silence tumour suppressor genes while activating other genes that enable tumour development and progression[2, 3] This suggests the possibility that compounds capable of recognizing distinguishing structural or chemical features of chromatin could allow the targeting of vulnerable points in cancer cells[6]. Heavy metal centres allow distinct characteristics of coordination geometry, oxidation state and ligand exchange for fine-tuning reactivity and affinity properties of the compound[12], and whether one is focused on the structural biology, biochemistry or cellular localization, the presence of heavy atoms can make visualization and quantification more accessible
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