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Title

Differential regulation of RNF8-mediated Lys48-and Lys63-based poly-ubiquitylation

AuthorsThomson, Timothy M. ; Huen, Michael S. Y.
Issue Date2012
PublisherOxford University Press
CitationNucleic Acids Research 40(1): 196-205 (2012)
AbstractPairing of a given E3 ubiquitin ligase with different E2s allows synthesis of ubiquitin conjugates of different topologies. While this phenomenon contributes to functional diversity, it remains largely unknown how a single E3 ubiquitin ligase recognizes multiple E2s, and whether identical structural requirements determine their respective interactions. The E3 ubiquitin ligase RNF8 that plays a critically important role in transducing DNA damage signals, interacts with E2s UBCH8 and UBC13, and catalyzes both K48-and K63-linked ubiquitin chains. Interestingly, we report here that a single-point mutation (I405A) on the RNF8 polypeptide uncouples its ability in catalyzing K48-and K63-linked ubiquitin chain formation. Accordingly, while RNF8 interacted with E2s UBCH8 and UBC13, its I405A mutation selectively disrupted its functional interaction with UBCH8, and impaired K48-based poly-ubiquitylation reactions. In contrast, RNF8 I405A preserved its interaction with UBC13, synthesized K63-linked ubiquitin chains, and assembled BRCA1 and 53BP1 at sites of DNA breaks. Together, our data suggest that RNF8 regulates K48-and K63-linked poly-ubiquitylation via differential RING-dependent interactions with its E2s UBCH8 and UBC13, respectively. © 2011 The Author(s).
DescriptionThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.-- et al.
Publisher version (URL)http://dx.doi.org/10.1093/nar/gkr655
URIhttp://hdl.handle.net/10261/52257
DOIhttp://dx.doi.org/10.1093/nar/gkr655
Identifiersdoi: 10.1093/nar/gkr655
issn: 0305-1048
e-issn: 1362-4962
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