Genome-wide maps of UV damage repair and mutation suppression by CPD photolyase

Ultraviolet (UV) light causes cyclobutane pyrimidine dimers (CPDs) and other DNA lesions that must be efficiently repaired to prevent cell death and mutagenesis. While mammals utilize the nucleotide excision repair (NER) pathway to repair CPDs, many species primarily utilize photolyase enzymes to repair UV damage. Our understanding of how different genomic and chromatin features impact photolyase repair across a eukaryotic genome is limited. Here, we map repair of CPDs by photolyase across the yeast genome at single-nucleotide resolution. Our data indicate that yeast photolyase repairs CPDs more rapidly than NER, but photolyase activity is inhibited at certain classes of transcription factor binding sites and in nucleosomes. Repair in nucleosomes is particularly inhibited when CPDs are located along the 3' side of the nucleosomal DNA or at minor-in rotational settings. Our data indicate that photolyase efficiently repairs the non-transcribed strand of yeast genes, but repair of the transcribed strand (TS) is inhibited. Genome-wide analysis of UV-induced mutations in NER-deficient photoreactivated yeast reveals a striking enrichment of mutations along the TS of yeast genes. These data indicate that inhibition of photolyase repair along the TS, likely due to occlusion of CPDs by RNA polymerase II stalling, promotes UV mutagenesis.