We recently developed two high-resolution methods for genome-wide mapping of two prominent types of DNA damage, single-strand DNA breaks (SSBs) and abasic (AP) sites and found highly complex and non-random patterns of these lesions in mammalian genomes. One salient feature of SSB and AP sites was the existence of single-nucleotide hotspots for both lesions. In this work, we show that SSB hotspots are enriched in the immediate vicinity of transcriptional start sites (TSSs) in multiple normal mammalian tissues, however the magnitude of enrichment varies significantly with tissue type and appears to be limited to a subset of genes. SSB hotspots around TSSs are enriched on the template strand and associate with higher expression of the corresponding genes. Interestingly, SSB hotspots appear to be at least in part generated by the base-excision repair (BER) pathway from the AP sites. Our results highlight complex relationship between DNA damage and regulation of gene expression and suggest an exciting possibility that SSBs at TSSs might function as sensors of DNA damage to activate genes important for DNA damage response.

中文翻译：

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转录起始位点常见的单链 DNA 断裂热点

我们最近开发了两种高分辨率方法，用于两种主要类型的 DNA 损伤、单链 DNA 断裂 (SSB) 和脱碱基 (AP) 位点的全基因组图谱，并在哺乳动物基因组中发现了这些损伤的高度复杂和非随机模式。 。 SSB 和 AP 位点的一个显着特征是两个病变均存在单核苷酸热点。在这项工作中，我们发现 SSB 热点在多个正常哺乳动物组织中的转录起始位点 (TSS) 附近富集，但富集的程度随组织类型的不同而显着变化，并且似乎仅限于基因的子集。 TSS 周围的 SSB 热点在模板链上富集，并与相应基因的较高表达相关。有趣的是，SSB 热点似乎至少部分是由 AP 位点的碱基切除修复 (BER) 途径产生的。我们的结果强调了 DNA 损伤和基因表达调控之间的复杂关系，并提出了一种令人兴奋的可能性，即 TSS 上的 SSB 可能充当 DNA 损伤的传感器，以激活对 DNA 损伤反应重要的基因。