title: Global genome nucleotide excision repair is organized into domains that promote 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 organized 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) subpathway, 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 organized 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; this has implications for the effects of chromatin modifiers on the distribution of mutations that arise throughout the genome.
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Shirong
authors.initials: S
authors.lastname: Yu
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Katie
authors.initials: K
authors.lastname: Evans
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Patrick
authors.identifier: 0000-0001-9549-555X
authors.initials: P
authors.lastname: van Eijk
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Bennett
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Webster
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Leadbitter
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Raymond
authors.initials: R
authors.lastname: Waters
authors.affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.
authors.forename: Stephen P
authors.identifier: 0000-0001-9317-7937
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
authors.forename: Simon H
authors.identifier: 0000-0002-4711-0560
authors.initials: SH
authors.lastname: Reed
mesh_terms: D000107:Acetylation; D002843:Chromatin / Q000235:genetics*; D004260:DNA Repair; D016681:Genome, Fungal; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D059645:Mutation Rate; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D002843:Chromatin; D051548:Histone Acetyltransferases; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor