Sequence Dependent UV Damage of ACACNNNNNNNNACAC ssDNA
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB59320 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10809431.fastq.gz | Fastqsanger.gz | |||
| ERR10809432.fastq.gz | Fastqsanger.gz | |||
| ERR10809433.fastq.gz | Fastqsanger.gz | |||
| ERR10809434.fastq.gz | Fastqsanger.gz | |||
| ERR10809435.fastq.gz | Fastqsanger.gz |
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Project description:UV-induced DNA damage is the major carcinogen of skin cancer. We developed HS-Damage-seq to map UV damage with unprecedented sensitivity and resolution in human cells. While the distribution of UV-induced damage are mainly determined by sequence context and essentially uniform throughout the genome, transcription factors can affect damage formation at specific positions. With time-course experiments, we observed changes in damage distribution at particular genomic loci and chromatin states, which reflects the nucleotide excision repair preferences and complements the repair maps by XR-seq. Our results demonstrated that while initial damage is uniformly distributed, they are heterogeneously repaired throughout the genome. The combination of damage and repair maps provides a holistic perspective of UV damage and repair in the human genome.
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Project description:UV-induced DNA lesions are an important contributor to mutagenesis and cancer, but it is not fully understood how the chromosomal landscape influences UV lesion formation and repair. We have used a novel high-throughput sequencing method to precisely map UV-induced cyclobutane pyrimidine dimers (CPDs) at nucleotide resolution throughout the yeast genome. Analysis of CPD formation reveals that nucleosomal DNA having an inward rotational setting is protected from CPD lesions. In strongly positioned nucleosomes, this nucleosome 'photofootprint' overrides intrinsic dipyrimidine sequence preferences for CPD formation. CPD formation is also inhibited by DNA-bound transcription factors, in effect protecting important DNA elements from UV damage. Analysis of CPD repair revealed a clear signature of efficient transcription-coupled nucleotide excision repair. Repair was less efficient at translational positions near a nucleosome dyad and at heterochromatic regions in the yeast genome. These findings define the roles of nucleosomes and transcription factors in UV damage formation and repair. UV mapping data was analyzed for yeast cells irradiated with 125J/m2 and allowed to repair for 0hr (2 samples), 20 minutes, 1 hour, or 2 hours. Data is also included for naked DNA irradiated with UV 60 or 90 J/m2
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Project description:These findings reveal the global chromatin response to UV damage and its relation to impaired gene regulation
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Project description:UV-induced DNA lesions are an important contributor to mutagenesis and cancer, but it is not fully understood how the chromosomal landscape influences UV lesion formation and repair. We have used a novel high-throughput sequencing method to precisely map UV-induced cyclobutane pyrimidine dimers (CPDs) at nucleotide resolution throughout the yeast genome. Analysis of CPD formation reveals that nucleosomal DNA having an inward rotational setting is protected from CPD lesions. In strongly positioned nucleosomes, this nucleosome 'photofootprint' overrides intrinsic dipyrimidine sequence preferences for CPD formation. CPD formation is also inhibited by DNA-bound transcription factors, in effect protecting important DNA elements from UV damage. Analysis of CPD repair revealed a clear signature of efficient transcription-coupled nucleotide excision repair. Repair was less efficient at translational positions near a nucleosome dyad and at heterochromatic regions in the yeast genome. These findings define the roles of nucleosomes and transcription factors in UV damage formation and repair.
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Project description:DNA damage repair systems are critical for genomic integrity. However, they must be coordinated with DNA replication and cell division to ensure accurate genomic transmission. In most bacteria this coordination is mediated by the SOS response through LexA , which triggers a halt in cell division until repair is completed. Recently, an SOS-independent damage response system was revealed in Caulobacter crescentus. This pathway is controlled by the transcription activator, DriD, but how DriD senses and signals DNA damage is unknown. To address this question we performed biochemical, cellular, and structural studies. We show that DriD binds a specific promoter DNA site via its N-terminal HTH domain to activate transcription of genes including the cell division inhibitor didA. A structure of the C-terminal portion of DriD revealed a WYL-motif domain linked to a WCX dimerization domain. Strikingly, we found that DriD binds ssDNA between the WYL and WCX domains. Comparison of apo and ssDNA-bound DriD reveals that ssDNA binding orders and orients the DriD domains, indicating a mechanism for ssDNA-mediated DNA-binding activation. Biochemical and in vivo studies support the structural model. Our data indicate this as a conserved mechanism of signaling for WYL-containing regulators.
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Project description:Ultraviolet (UV) light induces the formation of bulky UV photoproducts in the genome that interfere with DNA replication and transcription. It is well-established how human cells repair UV light-induced DNA lesions, however the signaling pathways and mechanisms that regulate transcription after exposure to UV light are poorly understood. Here, we provide a systematic view on dynamic protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on canonical DNA damage kinases and the p38 MAP kinase pathway. Notably, we demonstrate that p38 and its downstream effector kinase MK2 are responsible for one quarter of protein phosphorylation induced by UV light. We identify RNA binding proteins as primary targets and 14-3-3 family proteins as direct readers of UV light-induced, p38-MK2-dependent phosphorylation. Importantly, we demonstrate that UV light triggers rapid and dynamic phosphorylation of the negative elongation factor (NELF) complex subunit NELFE on serine 115 that mediates its binding to 14-3-3. NELFE interaction with 14-3-3 stabilizes NELFE and RNA pol II interaction on the chromatin and inhibits transcriptional elongation, thereby promoting cell survival after UV light.
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Project description:Ultraviolet (UV) light induces the formation of bulky UV photoproducts in the genome that interfere with DNA replication and transcription. It is well-established how human cells repair UV light-induced DNA lesions, however the signaling pathways and mechanisms that regulate transcription after exposure to UV light are poorly understood. Here, we provide a systematic view on dynamic protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on canonical DNA damage kinases and the p38 MAP kinase pathway. Notably, we demonstrate that p38 and its downstream effector kinase MK2 are responsible for one quarter of protein phosphorylation induced by UV light. We identify RNA binding proteins as primary targets and 14-3-3 family proteins as direct readers of UV light-induced, p38-MK2-dependent phosphorylation. Importantly, we demonstrate that UV light triggers rapid and dynamic phosphorylation of the negative elongation factor (NELF) complex subunit NELFE on serine 115 that mediates its binding to 14-3-3. NELFE interaction with 14-3-3 stabilizes NELFE and RNA pol II interaction on the chromatin and inhibits transcriptional elongation, thereby promoting cell survival after UV light.
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Project description:DNA damage caused by UV radiation initiates cellular recovery mechanisms, which involve activation of DNA damage response pathways, cell cycle arrest and apoptosis. To assess cellular transcriptional responses to UVC-induced DNA damage we compared time course responses of human skin fibroblasts to low and high doses of UVC radiation known to induce a transient cellular replicative arrest or apoptosis, respectively. UVC radiation elicited >3-fold changes in 460 out of 12,000 transcripts and 89% of these represented downregulated transcripts. Only 5% of the regulated genes were common to both low and high doses of radiation. Cells inflicted with a low dose of UVC exhibited transcription profiles demonstrating transient regulation followed by recovery, whereas the responses were persistent after the high dose. A detailed clustering analysis and functional classification of the targets implied regulation of biologically divergent responses and suggested involvement of transcriptional and translational machinery, inflammatory, anti-proliferative and anti-angiogenic responses. The data support the notion that UVC radiation induces prominent, dose-dependent downregulation of transcription. However, the data strongly suggest that transcriptional repression is also target gene selective. Furthermore, the results demonstrate that dose-dependent induction of cell cycle arrest and apoptosis by UVC radiation are transcriptionally highly distinct responses. Keywords: other
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Project description:Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here, we employ quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light, and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA binding proteins as primary substrates and 14-3-3 as direct readers of p38-MK2-dependent phosphorylation induced by UV light. Mechanistically, we show that MK2 phosphorylates the RNA binding subunit of the NELF complex NELFE on Serine 115. NELFE phosphorylation promotes the recruitment of 14-3-3 and rapid dissociation of the NELF complex from chromatin, which is accompanied by RNA polymerase II elongation.
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Project description:UV light is an initiating factor in the etiology of human melanoma due to its production of mutagenic DNA photoproducts, primarily cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts. UV-induced mutations are heterogeneously distributed across melanoma genomes, being enriched, for example, in regions of compact heterochromatin and at active transcription factor binding sites (TFBS). Differential ability of nucleotide excision repair (NER) to remove UV-induced DNA lesions in these regions has been proposed as the primary factor establishing the observed regional differences in melanoma mutation density. However, it is not fully understood to what extent the binding of transcription factors and chromatin structure affect UV damage formation, nor how variations in initial damage levels contribute to mutagenesis. Here, we directly mapped sites of CPD formation across the genome in human cells, and show that variations in UV damage formation, due to primary chromatin structure and transcription factor binding, are strongly correlated with local differences in melanoma mutation density. Analysis of individual transcription factors revealed that the E26 transformation-specific (ETS) family is the major contributor to increased somatic mutation density at TFBS in melanoma, primarily because DNA binding by ETS family transcription factors stimulates the formation of CPD lesions, generating UV damage 'hotspots'. Moreover, many ETS binding sites, including those associated with known cancer genes, are recurrently mutated in human melanomas. These findings establish variable lesion formation as a key contributor to mutation heterogeneity in cancer.
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