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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,11,26]]},"abstract":"<jats:p>\n                    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\u2032 terminal oligopyrimidine-tract translation regulation. The second occurs at A\n                    <jats:sub>2\u201315<\/jats:sub>\n                    TTCTY, which developed \u201cdark CPDs\u201d 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 sunburn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the \u223c20 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1907860116","type":"journal-article","created":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T20:10:03Z","timestamp":1573675803000},"page":"24196-24205","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":99,"title":["Genomic sites hypersensitive to ultraviolet radiation"],"prefix":"10.1073","volume":"116","author":[{"given":"Sanjay","family":"Premi","sequence":"first","affiliation":[{"name":"Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520-8040;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520-8040;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3029-3217","authenticated-orcid":false,"given":"Sameet","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06520-8005;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Knight","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06520-8005;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06520-8005;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meg A.","family":"Palmatier","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520-8040;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Kornacker","sequence":"additional","affiliation":[{"name":"Karl Kornacker &amp; Associates, LLC, Worthington, OH 43085;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas E.","family":"Brash","sequence":"additional","affiliation":[{"name":"Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520-8040;"},{"name":"Department of Dermatology, Yale School of Medicine, New Haven, CT 06520-8059;"},{"name":"Yale Cancer Center, Yale School of Medicine, New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,11,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"10571","DOI":"10.1073\/pnas.162278199","article-title":"Clusters of transcription-coupled repair in the human genome","volume":"99","author":"Surrall\u00e9s J.","year":"2002","unstructured":"J. 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