Abstract
Ultraviolet (UV) light-induced mutations are unevenly distributed across skin cancer genomes, but the molecular mechanisms responsible for this heterogeneity are not fully understood. Here, we assessed how nucleosome structure impacts the positions of UV-induced mutations in human melanomas. Analysis of mutation positions from cutaneous melanomas within strongly positioned nucleosomes revealed a striking ~10 base pair (bp) oscillation in mutation density with peaks occurring at dinucleotides facing away from the histone octamer. Additionally, higher mutation density at the nucleosome dyad generated an overarching “translational curvature” across the 147 bp of DNA that constitutes the nucleosome core particle. This periodicity and curvature cannot be explained by sequence biases in nucleosomal DNA. Instead, our genome-wide map of UV-induced cyclobutane pyrimidine dimers (CPDs) indicates that CPD formation is elevated at outward facing dinucleotides, mirroring the oscillation of mutation density within nucleosome-bound DNA. Nucleotide excision repair (NER) activity, as measured by XR-seq, inversely correlated with the curvature of mutation density associated with the translational setting of the nucleosome. While the 10 bp periodicity of mutations is maintained across nucleosomes regardless of chromatin state, histone modifications, and transcription levels, overall mutation density and curvature across the core particle increased with lower transcription levels. Our observations suggest structural conformations of DNA promote CPD formation at specific sites within nucleosomes, and steric hindrance progressively limits lesion repair towards the nucleosome dyad. Both mechanisms create a unique extended mutation signature within strongly positioned nucleosomes across the human genome.
Highlights
While it is known that mutation density correlates with chromatin compaction on a large scale, recent studies have suggested
UV light causes the formation of cyclobutane pyrimidine dimers (CPDs) and, to a lesser extent, 6–4 photoproducts (6-4PPs) [1], which can induce mutations that promote the development of melanomas and other skin cancers [2]
We show that mutation density in melanoma has a unique oscillatory pattern in strongly positioned nucleosomes, with peaks in mutation density occurring at regular ~10 bp intervals at outward rotational settings in nucleosomes
Summary
UV light causes the formation of cyclobutane pyrimidine dimers (CPDs) and, to a lesser extent, 6–4 photoproducts (6-4PPs) [1], which can induce mutations that promote the development of melanomas and other skin cancers [2]. Due to UV-induced mutagenesis, cutaneous melanomas typically have an extremely high number of base substitutions [5]. These somatic mutations are unevenly distributed across the cancer genome [6,7,8,9,10], despite little to no selective pressure occurring on the vast majority of these genetic changes. To better understand the molecular etiology of human skin cancers, it is important to elucidate the mechanisms that shape the genomic “landscape” of UV-induced mutation
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