Genomic sites hypersensitive to ultraviolet radiation
Genomic sites hypersensitive to ultraviolet radiation
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DOI：
10.1073/pnas.1907860116
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发表时间：
2019-11-26
影响因子：
11.1
通讯作者：
Brash, Douglas E.
中科院分区：
文献类型：
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作者：
Premi, Sanjay;Han, Lynn;Brash, Douglas E.
如果基因组包含对环境因素异常敏感的异常序列，这些序列将成为监测个人致癌物暴露的哨兵，并可能驱动细胞生理学的直接变化，而不是通过罕见的突变发挥作用。新方法 adductSeq 和 freqSeq 提供了统计分辨率，可以在整个基因组中以单碱基分辨率量化罕见病变。原代人黑素细胞（而非成纤维细胞）携带自发性无嘌呤位点和 TG 序列损伤，其频率比紫外线 (UV) 诱导的环丁烷嘧啶二聚体 (CPD) 更频繁。紫外线照射揭示了超热点获得 CPD 的频率比基因组平均值高出 170 倍；这些位点在黑素细胞中更为普遍。超热点不成比例地位于基因附近，特别是对于 RNA 结合蛋白，最常见的超热点位于 2 个 motlf 内的固定位置。一个基序出现在 ETS 家族转录因子结合位点（已知是 UV 靶点，现在被证明是基因组中最敏感的位点之一）以及 mTOR/5' 末端寡嘧啶束翻译调节位点。第二个发生在 A(2-)(15) TTCTY，它在紫外线照射后很长时间内形成“暗 CPD”，缓慢修复 CPD，并在实验前积累了 CPD。作为超热点活跃的基序位置在细胞类型之间有所不同。黑色素细胞 CPD 超热点与黑色素瘤个体基因启动子中反复出现的紫外线特征突变以及已知的癌症驱动因素精确对齐。在紫外线照射的晒伤水平下，每个细胞在大约 20 个目标细胞通路中的每一个中都会有一个超热点 CPD，让超热点充当表观遗传标记，造成表型不稳定；高患病率有利于同时发生突变，这将使肿瘤进化能够使用较弱的驱动因素。
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 motlfs. 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 A(2-)(15) TTCTY, 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 sunburn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the similar to 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.