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

TitleDifferential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation
Authors
Issue Date2012
PublisherOxford University Press. The Journal's web site is located at http://nar.oxfordjournals.org/
Citation
Nucleic Acids Research, 2012, v. 40 n. 1, p. 196-205 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/149773
ISSN
2023 Impact Factor: 16.6
2023 SCImago Journal Rankings: 7.048
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Seed Funding for Applied Research201007160001
URC-PDF, Centre for Cancer Research HKU
Faculty Development Fund
University of Hong Kong201007160001
Funding Information:

Seed Funding for Applied Research (Project No. 201007160001 to M.S.Y.H.); URC-PDF Scheme, Centre for Cancer Research HKU [to S. M. H. S. and S. S. D. (in part)]; Faculty Development Fund. Funding for open access charge: Seed Funding for Applied Research, University of Hong Kong (Project No. 201007160001 to M.S.Y.H.).

References
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DC FieldValueLanguage
dc.contributor.authorLok, GTMen_US
dc.contributor.authorSy, SMHen_US
dc.contributor.authorDong, SSen_US
dc.contributor.authorChing, YPen_US
dc.contributor.authorTsao, SWen_US
dc.contributor.authorThomson, TMen_US
dc.contributor.authorHuen, MSYen_US
dc.date.accessioned2012-06-26T05:58:23Z-
dc.date.available2012-06-26T05:58:23Z-
dc.date.issued2012en_US
dc.identifier.citationNucleic Acids Research, 2012, v. 40 n. 1, p. 196-205en_US
dc.identifier.issn0305-1048en_US
dc.identifier.urihttp://hdl.handle.net/10722/149773-
dc.description.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.en_US
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://nar.oxfordjournals.org/en_US
dc.relation.ispartofNucleic Acids Researchen_US
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshLysine - metabolismen_US
dc.subject.meshUbiquitin-Protein Ligases - chemistry - genetics - metabolismen_US
dc.subject.meshUbiquitinationen_US
dc.titleDifferential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylationen_US
dc.typeArticleen_US
dc.identifier.emailSy, SMH: mhsy@hku.hken_US
dc.identifier.emailDong, SS: dongss@hku.hken_US
dc.identifier.emailChing, YP: ypching@hku.hk-
dc.identifier.emailTsao, SW: gswtsao@hku.hk-
dc.identifier.emailHuen, MSY: huen.michael@hku.hk-
dc.identifier.authorityChing, YP=rp00469en_US
dc.identifier.authorityTsao, SW=rp00399en_US
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1093/nar/gkr655en_US
dc.identifier.pmid21911360-
dc.identifier.pmcidPMC3245915-
dc.identifier.scopuseid_2-s2.0-82955164827en_US
dc.identifier.hkuros198263-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-82955164827&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume40en_US
dc.identifier.issue1en_US
dc.identifier.spage196en_US
dc.identifier.epage205en_US
dc.identifier.eissn1362-4962-
dc.identifier.isiWOS:000298733500025-
dc.publisher.placeUnited Kingdomen_US
dc.relation.projectMonitoring DNA damage Using a Novel Fluorescence-based Biosensor: A platform for Drug Discovery and Genotoxic Evaluations-
dc.identifier.scopusauthoridHuen, MSY=23004751500en_US
dc.identifier.scopusauthoridThomson, TM=7005594330en_US
dc.identifier.scopusauthoridTsao, SW=54881406400en_US
dc.identifier.scopusauthoridChing, YP=7005431277en_US
dc.identifier.scopusauthoridDong, SS=35788109500en_US
dc.identifier.scopusauthoridSy, SMH=54901413200en_US
dc.identifier.scopusauthoridLok, GTM=44161157700en_US
dc.identifier.issnl0305-1048-

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