The effects of replication domains on the genome-wide UV-induced DNA damage and repair

Nucleotide excision repair is the primary repair mechanism that removes UV-induced DNA lesions in placentals. If the UV-induced pyrimidine dimers are left unrepaired they might turn into mutations during DNA replication. Although the mutagenesis of pyrimidine dimers is reasonably well understood, the direct effects of replication fork progress on nucleotide excision repair is yet to be clarified. Here, we applied Damage-seq and XR-seq techniques to measure damage and repair events in synchronized HeLa cells and integrated these data with replication maps that we generated under UV-induced experimental conditions. The results indicated that early replication domains were repaired faster, while ongoing replication could stimulate local nucleotide excision repair in both early and late replication domains by relaxing surrounding chromatin. On the other hand, it was unveiled that lesions on lagging strand templates were repaired slower in late replication domains, which was probably due to the imbalanced sequence context rather than a direct consequence of ongoing replication. Moreover, this differential damage and repair was in line with the strand bias of melanoma mutations, suggesting a role of exogenous damage, repair and replication in the mutational strand asymmetry.