The RNF168 paralog RNF169 defines a new class of ubiquitylated-histone reader involved in the response to DNA damage
- University of Toronto, Canada
- Mount Sinai Hospital, Canada
- University of Cambridge, United Kingdom
- The Francis Crick Research Institute, United Kingdom
- Leiden University, Netherlands
Abstract
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.
Article and author information
Author details
Michele Vendruscolo
Funding
Canadian Institutes of Health Research (RN203972 - 310401)
- Lewis E Kay
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ivan Dikic, Goethe University School of Medicine, Germany
Version history
- Received: December 2, 2016
- Accepted: April 12, 2017
- Accepted Manuscript published: April 13, 2017 (version 1)
- Version of Record published: May 11, 2017 (version 2)
Copyright
© 2017, Kitevski-LeBlanc et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The RNF168 paralog RNF169 defines a new class of ubiquitylated-histone reader involved in the response to DNA damage
eLife 6:e23872.
https://doi.org/10.7554/eLife.23872
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