Genome-wide mapping of DNA damage hotspots in response to various replication stressors
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ABSTRACT:
PROVIDER: PRJNA449770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6986060_1.fastq.gz | Fastqsanger.gz | |||
| SRR6986060_2.fastq.gz | Fastqsanger.gz | |||
| SRR6986070_1.fastq.gz | Fastqsanger.gz | |||
| SRR6986070_2.fastq.gz | Fastqsanger.gz | |||
| SRR6986061_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The goal of this study is to profile and identify DNA damage hotspots that are sensitive to different replication stressors.
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Project description:DNA damage hotspots for the Top2i "ICRF193"
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Project description:Excision repair hotspots of UV-induced DNA damage in the human genome
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Project description:Cells activate various stress response pathways when exposed to chemicals that can damage cellular macromolecules and organelles. Whether different chemical stressors activate common and/or stressor-specific pathways and to what extent is largely unclear. Here, we used quantitative phosphoproteomics to compare the phosphorylation signaling cascades induced by four stressors with different modes of action: the DNA damaging agent: cisplatin (CDDP), the topoisomerase II inhibitor: etoposide (ETO), the pro-oxidant: diethyl maleate (DEM) and the immunosuppressant: cyclosporine A (CsA). We show that equitoxic doses of these stressors induce distinctive and complex phosphorylation signaling cascades. Our results reveal stressor-specific kinase motifs and pathways. CDDP activates the DNA damage response (DDR) predominantly through the replication-stress related Atr kinase, whereas ETO triggers the DDR through Atr as well as the DNA double stranded break associated Atm kinase. CsA shares with ETO, a strong activation of CK2 kinase and significant Atm phosphorylation but lacks prominent activation of the DDR. Congruent with their known modes of action, CsA-mediated signaling is related to down-regulation of pathways that control hematopoietic differentiation and immunity whereas oxidative stress is the most prominent initiator of DEM-modulated stress signaling. This study presents an unprecedented molecular insight into the activated phosphorylation signaling cascades after various types of stressors.
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Project description:Here we have used a combination of advanced proteomics and genomics approaches to investigate the extent and mechanisms of transcription factor cross-talk at genomic hotspots. We identify ~12,000 transcription factor hotspots in the early phase of adipogenesis, and we find evidence of both simultaneous and sequential binding of transcription factors at these regions. We demonstrate for the first time that hotspots are highly enriched in large super-enhancer regions and that these drive the early adipogenic reprogramming of gene expression. Our results indicate that cooperativity between transcription factors at the level of hotspots as well as super-enhancers is very important for enhancer activity and transcriptional reprogramming. Thus, hotspots and super-enhancers constitute important regulatory hubs integrating external stimuli on chromatin. Genome-wide profiling of transcription factor and co-factor binding, epigenomic marks, and gene expression in 3T3-L1 pre-adipocytes.
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