Dynamic maps of UV damage formation and repair for the human genome

Significance Nucleotide excision repair removes DNA damage caused by carcinogens, such as UV and anticancer drugs, such as cisplatin. We have developed two methods, high-sensitivity damage sequencing and excision repair sequencing that map the formation and repair of damage in the human genome at single-nucleotide resolution. The combination of dynamic damage and repair maps provides a holistic perspective of UV damage and repair of the human genome and has potential applications in cancer prevention and chemotherapy. Formation and repair of UV-induced DNA damage in human cells are affected by cellular context. To study factors influencing damage formation and repair genome-wide, we developed a highly sensitive single-nucleotide resolution damage mapping method [high-sensitivity damage sequencing (HS–Damage-seq)]. Damage maps of both cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PPs] from UV-irradiated cellular and naked DNA revealed that the effect of transcription factor binding on bulky adducts formation varies, depending on the specific transcription factor, damage type, and strand. We also generated time-resolved UV damage maps of both CPDs and (6-4)PPs by HS–Damage-seq and compared them to the complementary repair maps of the human genome obtained by excision repair sequencing to gain insight into factors that affect UV-induced DNA damage and repair and ultimately UV carcinogenesis. The combination of the two methods revealed that, whereas UV-induced damage is virtually uniform throughout the genome, repair is affected by chromatin states, transcription, and transcription factor binding, in a manner that depends on the type of DNA damage.

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