PDF(Pubmed)
Abstract：
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：我们最近开发了两种高分辨率方法，用于对两种突出的DNA损伤类型进行全基因组定位，单链DNA断裂（SSB）和无碱基（AP）位点，并在哺乳动物基因组中发现了这些病变的高度复杂和非随机模式。SSB和AP位点的一个显著特征是两个病变都存在单核苷酸热点。
结果：在这项工作中，我们显示SSB热点富集在多个正常哺乳动物组织的转录起始位点（TSS）附近，然而，富集的程度随组织类型而显著变化，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。
结论：我们的研究结果强调了DNA损伤与基因表达调控之间的复杂关系，并表明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。
结果：在这项工作中，我们显示SSB热点富集在多个正常哺乳动物组织的转录起始位点（TSS）附近，然而，富集的程度随组织类型而显著变化，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。
结论：我们的研究结果强调了DNA损伤与基因表达调控之间的复杂关系，并表明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。
