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2017 ; 56
(23
): 6483-6487
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Chromatin Regulates Genome Targeting with Cisplatin
#MMPMID28474855
Zacharioudakis E
; Agarwal P
; Bartoli A
; Abell N
; Kunalingam L
; Bergoglio V
; Xhemalce B
; Miller KM
; Rodriguez R
Angew Chem Int Ed Engl
2017[Jun]; 56
(23
): 6483-6487
PMID28474855
show ga
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 Pol? 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.
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