Year: 2017
Type: article
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.
Source: Angewandte Chemie
Institutions: Centre National de la Recherche Scientifique, Institut de Chimie des Substances Naturelles, Inserm, Université Paris Sciences et Lettres, Chimie et Biologie de la Cellule, Institut Curie, The University of Texas at Austin, Université Toulouse III - Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,790
OpenAlex ID: W4236673833