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| Status |
Public on Jun 21, 2018 |
| Title |
CPD-seq map of UV damage formation in human fibroblasts |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
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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| Overall design |
UV-induced cyclobutane pyrimidine dimers (CPDs) were mapped across the genome of NHF1 cells immediately following UV irradiation (0 hr time point) with doses of 100 J/m2 or 20 J/m2 of UVC light. As a control, isolated NHF1 genomic DNA (i.e., naked DNA) was irradiated in vitro with UV dose of 80 J/m2 of UVC light.
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| Contributor(s) |
Wyrick J, Mao P |
| Citation(s) |
29980679 |
| Submission date |
Sep 05, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
John J. Wyrick |
| E-mail(s) |
jwyrick@vetmed.wsu.edu
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| Phone |
509-335-8785
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| Organization name |
Washington State University
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| Department |
School of Molecular Biosciences
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| Street address |
Biotechnology Life Sciences 241
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| City |
Pullman |
| State/province |
WA |
| ZIP/Postal code |
99164 |
| Country |
USA |
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| Platforms (1) |
| GPL17303 |
Ion Torrent Proton (Homo sapiens) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA401738 |
| SRA |
SRP116921 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE103487_RAW.tar |
1.1 Gb |
(http)(custom) |
TAR (of BED, WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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