Premium
Chromatin Regulates Genome Targeting with Cisplatin
Author(s) -
Zacharioudakis Emmanouil,
Agarwal Poonam,
Bartoli Alexandra,
Abell Nathan,
Kunalingam Lavaniya,
Bergoglio Valérie,
Xhemalce Blerta,
Miller Kyle M.,
Rodriguez Raphaël
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201701144
Subject(s) - cisplatin , proliferating cell nuclear antigen , chromatin , dna damage , microbiology and biotechnology , dna ligase , dna replication , chemistry , dna repair , dna , ubiquitin , biology , biochemistry , genetics , gene , chemotherapy
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.