Chromatin Regulates Genome Targeting with Cisplatin

Emmanouil Zacharioudakis, Poonam Agarwal, Alexandra Bartoli, Nathan Abell, Lavaniya Kunalingam, Valérie Bergoglio, Blerta Xhemalce, Kyle M. Miller, Raphaël Rodriguez

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Cisplatin derivatives can form various types of DNA lesions (DNA-Pt) and trigger pleiotropic DNA damage responses. Here, we report a strategy to visualize DNA-Pt with high resolution, taking advantage of a novel azide-containing derivative of cisplatin we named APPA, a cellular pre-extraction protocol and the labeling of DNA-Pt by means of click chemistry in cells. Our investigation revealed that pretreating cells with the histone deacetylase (HDAC) inhibitor SAHA led to detectable clusters of DNA-Pt that colocalized with the ubiquitin ligase RAD18 and the replication protein PCNA. Consistent with activation of translesion synthesis (TLS) under these conditions, SAHA and cisplatin cotreatment promoted focal accumulation of the low-fidelity polymerase Polη that also colocalized with PCNA. Remarkably, these cotreatments synergistically triggered mono-ubiquitination of PCNA and apoptosis in a RAD18-dependent manner. Our data provide evidence for a role of chromatin in regulating genome targeting with cisplatin derivatives and associated cellular responses.

Original languageEnglish (US)
Pages (from-to)6483-6487
Number of pages5
JournalAngewandte Chemie - International Edition
Volume56
Issue number23
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Keywords

  • cancer
  • chromatin
  • cisplatin
  • click chemistry
  • histone deacetylase

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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