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

TitleDifferential damage and repair of DNA-adducts induced by anti-cancer drug cisplatin across mouse organs.
Publication TypeJournal Article
Year of Publication2019
AuthorsYimit, Askar, Ogun Adebali, Aziz Sancar, and Yuchao Jiang
JournalNat Commun
Volume10
Issue1
Pagination309
Date Published2019 01 18
ISSN2041-1723
KeywordsAnimals, Antineoplastic Agents, Cisplatin, DNA Adducts, DNA Damage, DNA Repair, Epigenomics, Female, Mice, Inbred C57BL, Organ Specificity, Sequence Analysis, RNA, Transcriptome
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.

DOI10.1038/s41467-019-08290-2
Alternate JournalNat Commun
Original PublicationDifferential damage and repair of DNA-adducts induced by anti-cancer drug cisplatin across mouse organs.
PubMed ID30659176
PubMed Central IDPMC6338751
Grant ListP01 CA142538 / CA / NCI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R01 ES027255 / ES / NIEHS NIH HHS / United States
R35 GM118102 / GM / NIGMS NIH HHS / United States
Project: