Genome instability is increased during DNA replication in the presence of the CPD UV photoproduct in transcriptionally active genes

Ultraviolet (UV) light primarily induces cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts (6-4 PPs) and increases the risk of melanoma developing with genome instability. Here, we show that DNA double-strand breaks (DSBs) associated with genome instability arise during DNA replication in the presence of CPDs. Whereas 6-4PPs, which induce γH2AX expression and cell-cycle arrest, are repaired before the onset of DNA replication, CPDs persist into S phase. We also show that these DSBs are induced in association with transcription-coupled nucleotide excision repair (TC-NER). These DSBs decrease after CPDs were partially repaired in active chromatin regions, but persist in inactive chromatin regions. Structure variants (SVs) and single nucleotide variants (SNVs) associated with the UV-related single-base substitution 7 (SBS7) signature are induced in UV-irradiated cells. Our results point to a pathway that may underlie the genomic alterations observed in human melanoma.