Differential Damage and Repair of DNA-adducts Induced by Anti-cancer Drug Cisplatin Across Mouse Organs

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jan 20

PMID 30659176

Citations 88

Authors

Askar Yimit

Ogun Adebali

Aziz Sancar

Yuchao Jiang

Affiliations

Soon will be listed here.

Abstract

The platinum-based drug cisplatin is a widely used first-line therapy for several cancers. Cisplatin interacts with DNA mainly in the form of Pt-d(GpG) di-adduct, which stalls cell proliferation and activates DNA damage response. Although cisplatin shows a broad spectrum of anticancer activity, its utility is limited due to acquired drug resistance and toxicity to non-targeted tissues. Here, by integrating genome-wide high-throughput Damage-seq, XR-seq, and RNA-seq approaches, along with publicly available epigenomic data, we systematically study the genome-wide profiles of cisplatin damage formation and excision repair in mouse kidney, liver, lung and spleen. We find different DNA damage and repair spectra across mouse organs, which are associated with tissue-specific transcriptomic and epigenomic profiles. The framework and the multi-omics data we present here constitute an unbiased foundation for understanding the mechanisms of cellular response to cisplatin. Our approach should be applicable for studying drug resistance and for tailoring cancer chemotherapy regimens.

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