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CPD-seq map of UV damage formation in human fibroblasts

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103487 | GEO | 2018/06/21

REPOSITORIES: GEO

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Analysis of UV-induced DNA damage in human cells using CPD-seq 2.0

Project description:Noncoding mutation hotspots have been identified in melanoma and many of them occur at the binding sites of E26 transformation-specific (ETS) proteins; however, their formation mechanism and functional impacts are not fully understood. Here, we used UV damage sequencing data and analyzed cyclobutane pyrimidine dimer (CPD) formation, DNA repair, and CPD deamination in human cells at single-nucleotide resolution. Our data shows prominent CPD hotspots immediately after UV irradiation at ETS binding sites, particularly at sites with a conserved TTCCGG motif, which correlate with mutation hotspots identified in cutaneous melanoma. Additionally, CPDs are repaired slower at ETS binding sites than in flanking DNA. Cytosine deamination in CPDs to uracil is suggested as an important step for UV mutagenesis. However, we found that CPD deamination is significantly suppressed at ETS binding sites, particularly for the CPD hotspot on the 5’ side of the ETS motif, arguing against a role for CPD deamination in promoting ETS-associated UV mutations. Finally, we analyzed a subset of frequently mutated promoters, including the ribosomal protein genes RPL13A and RPS20, and found that mutations in the ETS motif can significantly reduce the promoter activity. Thus, our data identifies high UV damage and low repair, but not CPD deamination, as the main mechanism for ETS-associated mutations in melanoma and uncover new roles of often-overlooked mutation hotspots in perturbing gene transcription.

2023-12-01 | GSE235483 | GEO

Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers

Project description:Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.

2018-12-03 | GSE119249 | GEO

CPD-seq mapping of UV damage formation and repair in yeast

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

2016-08-19 | E-GEOD-79977 | biostudies-arrayexpress

CPD-seq mapping of UV damage formation and repair in yeast

2016-08-19 | GSE79977 | GEO

Genome-wide CPD repair maps of Caenorhabditis elegans

Project description:We have adapted the eXcision Repair-sequencing (XR-seq) method to generate single-nucleotide resolution dynamic repair maps of UV-induced cyclobutane pyrimidine dimers (CPD) photoproducts in the Caenorhabditis elegans (C. elegans) genome.

2024-04-02 | GSE262486 | GEO

Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution

Project description:We developed a method for genome-wide mapping of DNA excision repair named XR-seq (eXcision Repair-seq). Human nucleotide excision repair generates two incisions surrounding the site of damage, creating a ~30-mer. In XR-seq, this fragment is isolated and subjected to high-throughput sequencing. We used XR-seq to produce stranded, nucleotide-resolution maps of repair of two UV-induced DNA damages in human cells, cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts ((6-4)PPs). In wild-type cells, CPD repair was highly associated with transcription, specifically with the template strand. Experiments in cells defective in either transcription-coupled excision repair or general excision repair isolated the contribution of each pathway to the overall repair pattern, and showed that transcription-coupled repair of both photoproducts occurs exclusively on the template strand. XR-seq maps capture transcription-coupled repair at sites of divergent gene promoters and bi-directional eRNA production at enhancers. XR-seq data also uncovered the repair characteristics and novel sequence preferences of CPDs and (6-4)PPs. XR-seq and the resulting repair maps will facilitate studies of the effects of genomic location, chromatin context, transcription, and replication on DNA repair in human cells. We have performed XR-seq for two types of UV-induced damages (CPD and (6-4)PP) in three different cell lines: NHF1, XP-C (XP4PA-SV-EB, GM15983)), and CS-B (CS1ANps3g2, GM16095). Two biological replicates were performed for each experiment, in which independent cell populations were UV treated and subjected to XR-seq.

2015-04-19 | E-GEOD-67941 | biostudies-arrayexpress

Homo sapiens

Project description:CPD-seq map of UV damage formation in human fibroblasts

| PRJNA401738 | ENA

UVDE-HS-seq mapping of UV-induced 6-4PPs and atypical TA photoproducts

Project description:We used a novel high-throughput sequencing method known as UVDE-HS-seq to map the formation of UV-induced 6-4 photoproducts (6-4PP) and atypical thymidine-adenine (TA) photoproducts at single nucleotide resolution across the yeast genome in wild-type cells. We also analyzed 6-4PP and TA photoproducts in UV-irradiated yeast genomic DNA (i.e., naked DNA).

2023-02-28 | GSE214217 | GEO

Saccharomyces cerevisiae

Project description:CPD-seq mapping of UV damage formation and repair in yeast

| PRJNA317543 | ENA

Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis

Project description:We recently developed a high-resolution genome wide assay for mapping DNA excision repair named eXcision Repair-sequencing (XR-seq) (GEO accession: GSE67941) We have now used this assay to assay the effect of chromatin state on DNA repair. Here we report the results of a time-course of the repair of the UV induced damages cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts [(6-4)PPs] in normal human skin fibroblasts. Comparison of this data to histone modification and DNA-seq maps (ENCODE) revealed initial repair of both damages is enriched in open and active chromatin states, whereas repair in heterochromatic and repressed chromatin states is relatively low and persists to later time points. We performed XR-seq for two types of UV induced damages (CPD and (6-4)PP) at multiple time points after UV irradiation, in normal NHF1, and CS-B (CS1ANps3g2, GM16095) fibroblast cell lines. Two biological replicates were performed for each experiment in which independent independent cell populations were UV treated and subjected to XR-seq. For assaying CPD repair, cells were irradiated with 10J/m2 and for assaying (6-4)PP cells were irradiated with 20J/m2. Raw data for the 1h time points of (6-4)PP repair are the same as in GEO accession GSE67941).

2016-03-15 | E-GEOD-76391 | biostudies-arrayexpress

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