The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage.
Canny, Marella D
van Ingen, Hugo
Arrowsmith, Cheryl H
eLife Sciences Publications, Ltd
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Kitevski-LeBlanc, J., Fradet-Turcotte, A., Kukic, P., Wilson, M. D., Portella Carbo, G., Yuwen, T., Panier, S., et al. (2017). The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage.. Elife, 6 https://doi.org/10.7554/eLife.23872
Site-specific histone ubiquitylation plays a central role in orchestrating the response to DNA double-strand breaks (DSBs). DSBs elicit a cascade of events controlled by the ubiquitin ligase RNF168, which promotes the accumulation of repair factors such as 53BP1 and BRCA1 on the chromatin flanking the break site. RNF168 also promotes its own accumulation, and that of its paralog RNF169, but how they recognize ubiquitylated chromatin is unknown. Using methyl-TROSY solution NMR spectroscopy and molecular dynamics simulations, we present an atomic resolution model of human RNF169 binding to a ubiquitylated nucleosome, and validate it by electron cryomicroscopy. We establish that RNF169 binds to ubiquitylated H2A-Lys13/Lys15 in a manner that involves its canonical ubiquitin-binding helix and a pair of arginine-rich motifs that interact with the nucleosome acidic patch. This three-pronged interaction mechanism is distinct from that by which 53BP1 binds to ubiquitylated H2A-Lys15 highlighting the diversity in site-specific recognition of ubiquitylated nucleosomes.
Humans, Ubiquitin-Protein Ligases, Histones, Cryoelectron Microscopy, Magnetic Resonance Spectroscopy, Protein Binding, DNA Breaks, Double-Stranded, Molecular Dynamics Simulation
European Commission (654812)
External DOI: https://doi.org/10.7554/eLife.23872
This record's URL: https://www.repository.cam.ac.uk/handle/1810/269292
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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