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Tissue-specific transcriptomic and epigenomic profiles explain differential damage and repair of anti-cancer drug cisplatin induced DNA-adducts across mouse organs

ABSTRACT: Tissue-specific transcriptomic and epigenomic profiles explain differential damage and repair of anti-cancer drug cisplatin induced DNA-adducts across mouse organs

PROVIDER: PRJNA481337 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7526040.fastq.gz	Fastqsanger.gz
	SRR7526050.fastq.gz	Fastqsanger.gz
	SRR7526060_1.fastq.gz	Fastqsanger.gz
	SRR7526060_2.fastq.gz	Fastqsanger.gz
	SRR7526041.fastq.gz	Fastqsanger.gz

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Tissue-specific transcriptomic and epigenomic profiles explain differential damage and repair of anti-cancer drug cisplatin induced DNA-adducts across mouse organs

Project description: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 pathway. Cisplatin DNA-adducts are primarily repaired by nucleotide excision repair system. Despite cisplatin shows a broad spectrum of anticancer activity, it has limitation of use due to acquired drug resistance and toxicity to nontargeted tissues. By integrating genome-wide high-throughput “damage-seq”, “XR-seq”, mRNA-seq approaches along with epigenomic data we studied the mechanism of action of cisplatin across the mouse genome in kidney, liver, lung and spleen. Genome-wide damage-seq data reveal that kidney is highest cisplatin-damage accumulation site, while spleen is lowest. Excision repair on transcribed strand (TS) and non-transcribed strand (NTS) in active genes is in positive correlation with gene transcription, and regarding to nucleotide excision repair efficiency, there is no significant difference across organs. Lastly, in response to cisplatin treatment ATM signaling is upregulated in kidney, liver and lung, while PKA signaling is downregulated across all organs. The methodology and data we presented here include four different mouse organs and three “omics” data, it unbiasedly constitutes a foundation for understanding the mechanism of cellular respond to cisplatin and by means of improving chemotherapy while reducing side effect to normal tissues.

2019-01-01 | GSE117167 | GEO

Base-resolution analysis of cisplatin-DNA adducts at the genome scale

Project description:Cisplatin, one of the most widely used anticancer drugs, crosslinks DNA and ultimately induces cell death. However, the genomic pattern of cisplatin-DNA adducts remains unknown, due to the lack of a reliable and sensitive genome-wide method. Here we present “cisplatin-seq” to identify genome-wide cisplatin crosslinking sites at base-resolution. Cisplatin-seq reveals that mitochondrial DNA is a preferred target of cisplatin. For nuclear genome, cisplatin-DNA adducts are enriched within promoters and regions harboring transcription termination sites. While the density of GG dinucleotide determines the initial crosslinking of cisplatin, binding of proteins to the genome largely contributes to the accumulative pattern of cisplatin-DNA adducts.

2016-10-20 | GSE84637 | GEO

Base-resolution analysis of cisplatin-DNA adducts at the genome scale

Project description:Base-resolution analysis of cisplatin-DNA adducts at the genome scale

| PRJNA330713 | ENA

Cisplatin DNA Damage and Repair Maps of the Human Genome at Single-nucleotide Resolution

Project description:Platinum chemotherapies induce damages in DNA that distort the helical structure. In human cells, these adducts are removed primarily by the Nucleotide Excision Repair pathway. In this study, we mapped both cisplatin and oxaliplatin induced damages and their repair at single nucleotide resolution across the human genome.

2016-09-16 | GSE82213 | GEO

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

Project description: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.

| S-EPMC6338751 | biostudies-literature

Long-Term Kinetic Analysis of the Effect of the Circadian Clock and Transcription on Repair of Cisplatin-DNA Adducts in Mouse Liver

Project description:Cisplatin is the most commonly used chemotherapeutic drug for treating solid tumors. However, its toxicity and the innate or acquired resistance of cancer cells to the drug limit its usefulness. Cisplatin kills cells by forming cisplatin-DNA adducts, most commonly in the form of Pt-d(GpG) diadduct. We recently showed that repair of this adduct within 2 hours following injection is controlled by two circadian programs: (1) The circadian clock controls transcription of 2000 genes in mouse liver and thereby controls repair of the transcribed strand of these genes via transcription coupled repair in a rhythmic fashion unique to each gene’s phase of transcription. (2) The basal excision repair activity itself is controlled by the circadian clock with a single phase at which the repair of the non-transcribed strand and the rest of the genome take place. Here, we have followed the repair kinetic for long periods genome-wide both globally and at single nucleotide resolution by the Excision Repair-sequencing (XR-seq) method to gain further insight into cisplatin DNA damage and repair with the aim of improving the therapeutic index of the drug. Our data show that transcription-driven repair is complete after two days, while completion of basal repair of nontranscribed strands, silent genes and intergenic regions requires weeks. In rhythmically controlled genes, oscillations of transcribed repair are observed up to 2 days post-injection, and in both constitutively transcribed and rhythmic genes, we see a trend in template strand repair with time from the 5’to 3’ end. These findings add to the complexity of circadian- and transcription-dependent and -independent control of repair exhibited by this model organism in response to cisplatin.

2019-06-24 | GSE132002 | GEO

HMGB1 interactome in prostate and ovarian cancer cells treated with cisplatin

Project description:Cisplatin is used in chemotherapy of prostate, ovary and other cancer types but unfortunately the efficiency of cisplatin treatment is frequently hampered by acquired resistance. The cytotoxic effect of cisplatin has been attributed to its binding to DNA. HMGB1 is able to bind to cisplatin-DNA adducts with high affinity and its expression levels are associated with cisplatin resistance. This study reports the interactome of HMGB1 in prostate and ovarian cancer cells treated with cisplatin.

2021-11-01 | PXD026309 | Pride

Transcriptomic analyses of IXR1 gene deletion in Saccharomyces cerevisiae and its increased resistance to cisplatin treatment.

Project description:Ixr1 is a transcriptional factor from Saccharomyces cerevisae with high affinity to cisplatin-DNA adducts through their two HMG-box DNA binding domains. Its transcriptional regulation is essential in the cytotoxicity caused by cisplatin, although the molecular mechanisms supporting this function are not understood. We present a transcriptome analysis discriminating between RNA changes induced by cisplatin which are dependent or independent of the Ixr1 function.

2018-02-21 | GSE84569 | GEO

Long-term, genome-wide kinetic analysis of the effect of the circadian clock and transcription on the repair of cisplatin-DNA adducts in the mouse liver

2019-06-24 | GSE132993 | GEO

Methylglyoxal-derived nucleoside adducts drive vascular dysfunction in a RAGE-dependent manner

Project description:Diabetic kidney disease (DKD) is a leading cause of death in patients with diabetes. An early precursor to DKD is endothelial cell dysfunction (ECD), a factor that often precedes and exacerbates vascular disease progression. We previously discovered that covalent adducts formed on DNA, RNA, and proteins by reactive metabolic by-product methylglyoxal (MG) predict DKD risk in patients with type 1 diabetes up to 16 years pre-diagnosis. However, the mechanisms by which MG-adducts contribute to vascular disease onset and progression remain unclear. Here, we report that the most predominant MG-induced nucleoside adducts, N2-(1-carboxyethyl)-deoxyguanosine (CEdG) and N2-(1-carboxyethyl)-guanosine (CEG), drive endothelial dysfunction. Following CEdG or CEG exposure, primary human umbilical vein endothelial cells (HUVECs) undergo endothelial dysfunction, resulting in enhanced monocyte adhesion, increased reactive oxygen species production, endothelial permeability, impaired endothelial homeostasis, and exhibit a dysfunctional transcriptomic signature. These effects were discovered to be mediated through the receptor for advanced glycation end products (RAGE), as an inhibitor for intracellular RAGE signaling diminished these dysfunctional phenotypes. Therefore, we find that not only are MG-adducts biomarkers for DKD, this study reveals they may also have a dual role as potential drivers of vascular disease onset and progression and a new therapeutic modality.

2024-01-19 | GSE251645 | GEO

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