A critical link in mapping recurrent mutations of melanoma -- the most serious form of skin cancer in humans -- has been discovered by researchers. In a paper published in Nature Communications, researchers established that DNA binding by a specific set of transcription factors, called E26 transformation-specific (ETS) TFs, is inherently mutagenic in UV-exposed cells. With new genome mapping technology, these findings provide a crucial understanding of mutations that result at ETS binding sites located in specific genes that are known to be drivers in the onset of melanoma in humans.
The researchers have developed a next-generation sequencing-based technology that allows them to precisely map the locations of UV-induced DNA damage (cyclobutane pyrimidine dimers, CPD) throughout the whole human genome. Using this advanced technology, they generated a high-resolution UV damage map in human cells. By correlating the UV damage map with melanoma mutations, they discovered significantly elevated UV damage levels at ETS binding sites, which massively increased mutation rates at the same sites in sequenced melanoma genomes.
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.
"UV-induced DNA damage is the major risk factor for melanoma, and DNA repair is a vital first line of defense against DNA damage to prevent mutations and cancer," stated the senior author. "These pivotal results establish a fundamental research tool in cancer research and confirms we are on the correct course to further discovery by mapping UV damage in human cells."
Mapping DNA damage links to onset of skin cancer
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