Nucleosome positions establish an extended mutation signature in melanoma

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2018

Erschienen:

2018

Enthalten in:

Zur Gesamtaufnahme - volume:14

Enthalten in:

PLoS genetics - 14(2018), 11 vom: 28. Nov., Seite e1007823

Sprache:

Englisch

Beteiligte Personen:

Brown, Alexander J [VerfasserIn]
Mao, Peng [VerfasserIn]
Smerdon, Michael J [VerfasserIn]
Wyrick, John J [VerfasserIn]
Roberts, Steven A [VerfasserIn]

Links:

Volltext

Themen:

Chromatin
DNA, Neoplasm
Journal Article
Nucleosomes
Pyrimidine Dimers
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Anmerkungen:

Date Completed 26.02.2019

Date Revised 09.03.2020

published: Electronic-eCollection

Citation Status MEDLINE

doi:

10.1371/journal.pgen.1007823

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM291163319