Super-hotspots and -coldspots in the repair of UV-induced DNA damage in the human genome.

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 [(6-4)PP] by using the eXcision Repair-sequencing (XR-seq) method. We further identified super-coldspots for (6-4)PP repair and super-hotspots for cyclobutane pyrimidine dimer (CPD) repair by analyzing available XR-seq time-course data. By integrating datasets of XR-seq, Damage-seq, adductSeq, and CPD-seq, we show that neither repair super-hotspots nor -coldspots overlap hotspots of UV damage. Furthermore, we demonstrate that repair super-hotspots are significantly enriched in frequently interacting regions (FIREs) and super-enhancers. Finally, we report our discovery of an enrichment of cytosine in repair super-hotspots and -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.