Journal article
Nucleosome positions establish an extended mutation signature in melanoma
PLoS genetics, Vol.14(11), pp.e1007823-e1007823
11/2018
Handle:
https://hdl.handle.net/2376/112177
PMCID: PMC6287878
PMID: 30485262
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.
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Details
- Title
- Nucleosome positions establish an extended mutation signature in melanoma
- Creators
- Alexander J Brown - School of Molecular Biosciences, Washington State University, Pullman, WA, United States of AmericaPeng Mao - School of Molecular Biosciences, Washington State University, Pullman, WA, United States of AmericaMichael J Smerdon - School of Molecular Biosciences, Washington State University, Pullman, WA, United States of AmericaJohn J Wyrick - Center for Reproductive Biology, Washington State University, Pullman, WA, United States of AmericaSteven A Roberts - Center for Reproductive Biology, Washington State University, Pullman, WA, United States of America
- Publication Details
- PLoS genetics, Vol.14(11), pp.e1007823-e1007823
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- United States
- Grant note
- T32 GM008336 / NIGMS NIH HHS R00 ES022633 / NIEHS NIH HHS R01 ES028698 / NIEHS NIH HHS R01 ES002614 / NIEHS NIH HHS R01 CA218112 / NCI NIH HHS R21 ES027937 / NIEHS NIH HHS
- Identifiers
- 99900547449201842
- Language
- English
- Resource Type
- Journal article