Title: Recurrent Noncoding Mutations in Skin Cancers: UV Damage Susceptibility or Repair Inhibition as Primary Driver?
Authors: Roberts, Steven A; Brown, Alexander J; Wyrick, John J
Published In Bioessays, (2019 03)
Abstract: Somatic mutations arising in human skin cancers are heterogeneously distributed across the genome, meaning that certain genomic regions (e.g., heterochromatin or transcription factor binding sites) have much higher mutation densities than others. Regional variations in mutation rates are typically not a consequence of selection, as the vast majority of somatic mutations in skin cancers are passenger mutations that do not promote cell growth or transformation. Instead, variations in DNA repair activity, due to chromatin organization and transcription factor binding, have been proposed to be a primary driver of mutational heterogeneity in melanoma. However, as discussed in this review here, recent studies indicate that chromatin organization and transcription factor binding also significantly modulate the rate at which UV lesions form in DNA. The authors propose that local variations in lesion susceptibility may be an important driver of mutational hotspots in melanoma and other skin cancers, particularly at binding sites for ETS transcription factors.
PubMed ID: 30801747
MeSH Terms: Binding Sites/genetics; DNA Damage/radiation effects*; DNA Repair/radiation effects*; Humans; Melanoma/genetics*; Mutagenesis/radiation effects; Mutation Rate; Mutation/radiation effects*; Nucleic Acid Conformation; Nucleosomes/radiation effects; Promoter Regions, Genetic/genetics; Proto-Oncogene Proteins c-ets/metabolism; Skin Neoplasms/genetics*; Ultraviolet Rays/adverse effects*