Abstract
Recurrent mutations are frequently associated with transcription factor (TF) binding sites (TFBS) in melanoma, but the mechanism driving mutagenesis at TFBS is unclear. Here, we use a method called CPD-seq to map the distribution of UV-induced cyclobutane pyrimidine dimers (CPDs) across the human genome at single nucleotide resolution. Our results indicate that CPD lesions are elevated at active TFBS, an effect that is primarily due to E26 transformation-specific (ETS) TFs. We show that ETS TFs induce a unique signature of CPD hotspots that are highly correlated with recurrent mutations in melanomas, despite high repair activity at these sites. ETS1 protein renders its DNA binding targets extremely susceptible to UV damage in vitro, due to binding-induced perturbations in the DNA structure that favor CPD formation. These findings define a mechanism responsible for recurrent mutations in melanoma and reveal that DNA binding by ETS TFs is inherently mutagenic in UV-exposed cells.
Highlights
Recurrent mutations are frequently associated with transcription factor (TF) binding sites (TFBS) in melanoma, but the mechanism driving mutagenesis at transcription factor binding sites (TFBS) is unclear
To test the hypothesis that variations in UV damage formation contribute to elevated mutation rates at TFBS, we analyzed mutation densities and UV damage levels at a welldefined set of TFBS for 82 distinct human TFs23, initially focusing on TFBS located in promoter regions
Using this much larger ICGC melanoma dataset[18], we confirmed that mutation density is significantly elevated near active TFBS (Fig. 1b), defined as TFBS that overlap with DNase I hypersensitive sites (DHS) in human melanocytes[11]
Summary
Recurrent mutations are frequently associated with transcription factor (TF) binding sites (TFBS) in melanoma, but the mechanism driving mutagenesis at TFBS is unclear. UV light induces the formation of cyclobutane pyrimidine dimers (CPDs) and, to a lesser extent, pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) at dipyrimidine sequences in DNA1 If unrepaired, these lesions can induce carcinogenic mutations that drive the development of skin cancers like melanoma. While variations in mutation density correlate with replication timing, transcription, and nucleotide excision repair (NER) activity, the detailed molecular mechanisms that shape the genomic landscape of UV-induced mutation density are unclear Elucidating these mechanisms is important, since they contribute to the etiology of recurrent driver mutations in human skin cancers. An increased frequency of UV damage at TFBS could contribute to elevated mutation rates; most TFs appear to suppress UV damage formation at their binding sites[13], likely by restricting the conformational flexibility of DNA needed to form CPD lesions. To determine how differences in the rate of UV damage formation influence mutagenesis at TFBS, it is important to accurately measure CPD lesions occurring in all dipyrimidine sequence contexts
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