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Nature. 2019 May 29. doi: 10.1038/s41586-019-1259-3. [Epub ahead of print]

DNA damage detection in nucleosomes involves DNA register shifting.

Author information

1
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
2
University of Basel, Basel, Switzerland.
3
Division of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Japan.
4
Biosignal Research Center, and Graduate School of Science, Kobe University, Kobe, Japan.
5
Laboratory of Chromatin Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
6
Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
7
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. nicolas.thoma@fmi.ch.
8
University of Basel, Basel, Switzerland. nicolas.thoma@fmi.ch.

Abstract

Access to DNA packaged in nucleosomes is critical for gene regulation, DNA replication and DNA repair. In humans, the UV-damaged DNA-binding protein (UV-DDB) complex detects UV-light-induced pyrimidine dimers throughout the genome; however, it remains unknown how these lesions are recognized in chromatin, in which nucleosomes restrict access to DNA. Here we report cryo-electron microscopy structures of UV-DDB bound to nucleosomes bearing a 6-4 pyrimidine-pyrimidone dimer or a DNA-damage mimic in various positions. We find that UV-DDB binds UV-damaged nucleosomes at lesions located in the solvent-facing minor groove without affecting the overall nucleosome architecture. In the case of buried lesions that face the histone core, UV-DDB changes the predominant translational register of the nucleosome and selectively binds the lesion in an accessible, exposed position. Our findings explain how UV-DDB detects occluded lesions in strongly positioned nucleosomes, and identify slide-assisted site exposure as a mechanism by which high-affinity DNA-binding proteins can access otherwise occluded sites in nucleosomal DNA.

PMID:
31142837
DOI:
10.1038/s41586-019-1259-3

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