Genomic sites hypersensitive to ultraviolet radiation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 48; pp. 24196 - 24205
• Main Authors: Premi, Sanjay, Han, Lynn, Mehta, Sameet, Knight, James, Zhao, Dejian, Palmatier, Meg A., Kornacker, Karl, Brash, Douglas E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.11.2019
• Series: PNAS Plus
• Subjects: 5' Untranslated Regions; Apurinic sites; Binding sites; Biological Sciences; Carcinogens; Cells, Cultured; Cyclobutane; Cyclobutane pyrimidine dimers; Dimers; DNA Damage - radiation effects; Epigenetics; ETS protein; Exposure; Fibroblasts; Fibroblasts - physiology; Fibroblasts - radiation effects; Gene expression; Gene Expression Regulation - radiation effects; Gene sequencing; Genome, Human - radiation effects; Genomes; High-Throughput Nucleotide Sequencing; Humans; Lesions; Melanocytes; Melanocytes - physiology; Melanocytes - radiation effects; Melanoma - genetics; Mutation; Outliers (statistics); PNAS Plus; Promoter Regions, Genetic; Protein Biosynthesis; Pyrimidine Dimers - radiation effects; Pyrimidine Nucleotides - radiation effects; Ribonucleic acid; RNA; RNA-binding protein; Skin Neoplasms - genetics; Sunburn; TOR protein; TOR Serine-Threonine Kinases - genetics; Ultraviolet radiation; Ultraviolet Rays; UV; melanoma; cyclobutane pyrimidine dimer; ETS; TOP tract
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1907860116

If the genome contains outlier sequences extraordinarily sensitive to environmental agents, these would be sentinels for monitoring personal carcinogen exposure and might drive direct changes in cell physiology rather than acting through rare mutations. New methods, adductSeq and freqSeq, provided statistical resolution to quantify rare lesions at single-base resolution across the genome. Primary human melanocytes, but not fibroblasts, carried spontaneous apurinic sites and TG sequence lesions more frequent than ultraviolet (UV)-induced cyclobutane pyrimidine dimers (CPDs). UV exposure revealed hyperhotspots acquiring CPDs up to 170-fold more frequently than the genomic average; these sites were more prevalent in melanocytes. Hyperhotspots were disproportionately located near genes, particularly for RNA-binding proteins, with the most-recurrent hyperhotspots at a fixed position within 2 motifs. One motif occurs at ETS family transcription factor binding sites, known to be UV targets and now shown to be among the most sensitive in the genome, and at sites of mTOR/5′ terminal oligopyrimidine-tract translation regulation. The second occurs at A2–15TTCTY, which developed “dark CPDs” long after UV exposure, repaired CPDs slowly, and had accumulated CPDs prior to the experiment. Motif locations active as hyperhotspots differed between cell types. Melanocyte CPD hyperhotspots aligned precisely with recurrent UV signature mutations in individual gene promoters of melanomas and with known cancer drivers. At sun-burn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the ∼20 targeted cell pathways, letting hyperhotspots act as epigenetic marks that create phenome instability; high prevalence favors cooccurring mutations, which would allow tumor evolution to use weak drivers.