Differential damage and repair of DNA-adducts induced by anti-cancer drug cisplatin across mouse organs

Askar Yimit, Ogun Adebali, Aziz Sancar () and Yuchao Jiang ()
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Askar Yimit: University of North Carolina at Chapel Hill
Ogun Adebali: Sabanci University
Aziz Sancar: University of North Carolina at Chapel Hill
Yuchao Jiang: University of North Carolina at Chapel Hill

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08290-2

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