Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
J Biol Chem. 2021 Jan-Jun;296:100581. doi: 10.1016/j.jbc.2021.100581. Epub 2021 Mar 23.
The formation of UV-induced DNA damage and its repair are influenced by many factors that modulate lesion formation and the accessibility of repair machinery. However, it remains unknown which genomic sites are prioritized for immediate repair after UV damage induction, and whether these prioritized sites overlap with hotspots of UV damage. We identified the super hotspots subject to the earliest repair for (6-4) pyrimidine-pyrimidone photoproduct by using the eXcision Repair-sequencing (XR-seq) method. We further identified super coldspots for (6-4) pyrimidine-pyrimidone photoproduct repair and super hotspots for cyclobutane pyrimidine dimer repair by analyzing available XR-seq time-course data. By integrating datasets of XR-seq, Damage-seq, adductSeq, and cyclobutane pyrimidine dimer-seq, we show that neither repair super hotspots nor repair super coldspots overlap hotspots of UV damage. Furthermore, we demonstrate that repair super hotspots are significantly enriched in frequently interacting regions and superenhancers. Finally, we report our discovery of an enrichment of cytosine in repair super hotspots and super coldspots. These findings suggest that local DNA features together with large-scale chromatin features contribute to the orders of magnitude variability in the rates of UV damage repair.
紫外线诱导的 DNA 损伤的形成及其修复受到许多因素的影响，这些因素调节损伤的形成和修复机制的可及性。然而，目前尚不清楚在紫外线损伤诱导后，哪些基因组位点优先进行即时修复，以及这些优先修复的位点是否与紫外线损伤热点重叠。我们使用切除修复测序（XR-seq）方法，确定了（6-4）嘧啶-嘧啶酮光产物最早修复的超级热点。通过分析现有的 XR-seq 时程数据，我们进一步确定了（6-4）嘧啶-嘧啶酮光产物修复的超级冷点和环丁烷嘧啶二聚体修复的超级热点。通过整合 XR-seq、损伤-seq、加合物-seq 和环丁烷嘧啶二聚体-seq 的数据集，我们表明，修复超级热点和修复超级冷点都与紫外线损伤热点不重叠。此外，我们证明修复超级热点在频繁相互作用区域和超级增强子中显著富集。最后，我们报告了在修复超级热点和超级冷点中发现胞嘧啶富集的现象。这些发现表明，局部 DNA 特征与大规模染色质特征共同导致紫外线损伤修复速率的巨大变异性。
