PT - JOURNAL ARTICLE AU - Anna R Poetsch AU - Simon J Boulton AU - Nicholas M Luscombe TI - Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis AID - 10.1101/168153 DP - 2017 Jan 01 TA - bioRxiv PG - 168153 4099 - http://biorxiv.org/content/early/2017/07/25/168153.short 4100 - http://biorxiv.org/content/early/2017/07/25/168153.full AB - DNA is subject to constant chemical modification and damage, which eventually results in variable mutation rates throughout the genome. Although detailed molecular mechanisms of DNA damage and repair are well-understood, damage impact and execution of repair across a genome remains poorly defined. To bridge the gap between our understanding of DNA repair and mutation distributions we developed a novel method, AP-seq, capable of mapping apurinic sites and 8oxoguanidine bases at high resolution on a genome-wide scale. We directly demonstrate that the accumulation rate of oxidative damage varies widely across the genome, with hot spots acquiring many times more damage than cold spots. Unlike SNVs in cancers, damage burden correlates with marks for open chromatin notably H3K9ac and H3K4me2. Oxidative damage is also highly enriched in transposable elements and other repetitive sequences. In contrast, we observe decreased damage at promoters, exons and termination sites, but not introns, in a seemingly transcription-independent manner. Leveraging cancer genomic data, we also find locally reduced SNV rates in promoters, genes and other functional elements. Taken together, our study reveals that oxidative DNA damage accumulation and repair differ strongly across the genome, but culminate in a previously unappreciated mechanism that safe-guards the regulatory sequences and the coding regions of genes from mutations.