Abstract
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.
Highlights
UV-induced DNA damage, if not removed efficiently, will lead to mutations and possibly carcinogenesis in humans
To identify which genomic sites are prioritized for nucleotide excision repair immediately after UV irradiation and which sites are subject to repair only at the latest stage of DNA damage removal, we designed an experimental and analytical framework to systematically investigate excision repair kinetics and UV damage formation over a time course
We have shown that global repair dominates cyclobutane pyrimidine dimer (CPD) removal in the first 12 min after UV irradiation in normal human skin fibroblast 1 (NHF1) cells, and at later time points, transcription-coupled repair (TCR) facilitates CPD removal (22)
Summary
To identify which genomic sites are prioritized for nucleotide excision repair immediately after UV irradiation and which sites are subject to repair only at the latest stage of DNA damage removal, we designed an experimental and analytical framework to systematically investigate excision repair kinetics and UV damage formation over a time course. The XR-seq signals at a super coldspot for (6-4)PP repair, shown, increase over the time course and peak at 4 h Another representative super hotspot for CPD repair is shown at 12 min (Fig. 2C). After stringent quality control procedures (refer to the Methods section for details), we identified 91 damage hotspots from the plus strand and 78 CPD damage hotspots from the minus strand, each with at least 10 mapped reads (Table S5) These CPD hotspots are shown to be enriched for heterochromatin and repressed regions (Fig. S7), which is concordant with previous reports (31, 40, 41). We compared the DNA damage levels for (6-4)PP and CPD from three independent sequencing technologies— Damage-seq (14), adductSeq (15), and CPD-seq (25)—at our identified repair super hotspots and super coldspots against those from randomly sampled regions over the genome. The rapid removal of DNA damage in repair super hotspots in critical regions of the genome may aid cellular survival
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