Global Genome Nucleotide Excision Repair is Organised into Domains Promoting Efficient DNA Repair in Chromatin

Abstract

The rates at which lesions are removed by DNA repair can vary widely throughout the genome with important implications for genomic stability. To study this, we measured the distribution of nucleotide excision repair (NER) rates for UV-induced lesions throughout the budding yeast genome. By plotting these repair rates in relation to genes and their associated flanking sequences, we reveal that in normal cells, genomic repair rates display a distinctive pattern, suggesting that DNA repair is highly organised within the genome. Furthermore, by comparing genome-wide DNA repair rates in wild-type cells, and cells defective in the global genome-NER (GG-NER) sub-pathway, we establish how this alters the distribution of NER rates throughout the genome. We also examined the genomic locations of GG-NER factor binding to chromatin before and after UV irradiation revealing that GG-NER is organised and initiated from specific genomic locations. At these sites, chromatin occupancy of the histone acetyl transferase Gcn5 is controlled by the GG-NER complex, which regulates histone H3 acetylation and chromatin structure, thereby promoting efficient DNA repair of UV-induced lesions. Chromatin remodeling during the GG-NER process is therefore organized into these genomic domains. Importantly, loss of Gcn5, significantly alters the genomic distribution of NER rates, a finding that has important implications for the effects of chromatin modifiers on the distribution of mutations that arise throughout the genome.