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Article: The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection

TitleThe E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection
Authors
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/nsmb/
Citation
Nature Structural And Molecular Biology, 2011, v. 18 n. 12, p. 1400-1407 How to Cite?
AbstractThe mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres. Here we show that in Mus musculus, the E3 ubiquitin ligase Rnf8 localizes to uncapped telomeres and promotes the accumulation of DNA damage proteins 53Bp1 and γ-H 2ax. In the absence of Rnf8, Tpp1 is unstable, resulting in telomere shortening and chromosome fusions through the alternative nonhomologous end-joining (A-NHEJ) repair pathway. The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. Thus, Tpp1 is a newly identified substrate for Rnf8, indicating a previously unrecognized role for Rnf8 in telomere end protection. © 2011 Nature America, Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/144509
ISSN
2015 Impact Factor: 13.338
2015 SCImago Journal Rankings: 12.548
ISI Accession Number ID
Funding AgencyGrant Number
National Cancer InstituteRO1 CA129037
Michael and Betty Kadoorie Cancer Genetic Research Program
Welch FoundationAU-1711
Funding Information:

We are grateful to J. Karlseder (Salk Institute) for providing anti-mouse Trf1 and Trf2 antibodies, to Z. Songyang (Baylor College of Medicine) for providing antihuman TPP1 antibody and TPP1 cDNA constructs and to D. Durocher (Samuel Lunenfeld Research Institute) for providing mouse Rnf8 and Rnf8 mutant cDNAs. The linkage-specific antibodies to Lys63 and Lys48 ubiquitin conjugates were provided by V.M. Dixit (Genentech), and pLPC-hRAP1 was a gift from M. Lei (University of Michigan Medical School). We would like to thank A. Multani (MD Anderson Cancer Center) for help with chromosome analysis and I. Patanam for technical support. S.C. acknowledges generous financial support from the National Cancer Institute (RO1 CA129037) and the Michael and Betty Kadoorie Cancer Genetic Research Program. J.J. is a Pew Scholar and is supported by a grant (AU-1711) from the Welch Foundation.

References

 

DC FieldValueLanguage
dc.contributor.authorRai, Ren_HK
dc.contributor.authorLi, JMen_HK
dc.contributor.authorZheng, Hen_HK
dc.contributor.authorLok, GTMen_HK
dc.contributor.authorDeng, Yen_HK
dc.contributor.authorHuen, MSYen_HK
dc.contributor.authorChen, Jen_HK
dc.contributor.authorJin, Jen_HK
dc.contributor.authorChang, Sen_HK
dc.date.accessioned2012-02-03T06:11:40Z-
dc.date.available2012-02-03T06:11:40Z-
dc.date.issued2011en_HK
dc.identifier.citationNature Structural And Molecular Biology, 2011, v. 18 n. 12, p. 1400-1407en_HK
dc.identifier.issn1545-9993en_HK
dc.identifier.urihttp://hdl.handle.net/10722/144509-
dc.description.abstractThe mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres. Here we show that in Mus musculus, the E3 ubiquitin ligase Rnf8 localizes to uncapped telomeres and promotes the accumulation of DNA damage proteins 53Bp1 and γ-H 2ax. In the absence of Rnf8, Tpp1 is unstable, resulting in telomere shortening and chromosome fusions through the alternative nonhomologous end-joining (A-NHEJ) repair pathway. The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. Thus, Tpp1 is a newly identified substrate for Rnf8, indicating a previously unrecognized role for Rnf8 in telomere end protection. © 2011 Nature America, Inc. All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/nsmb/en_HK
dc.relation.ispartofNature Structural and Molecular Biologyen_HK
dc.subject.meshAminopeptidases - chemistry - metabolismen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshChromosomal Proteins, Non-Histone - metabolismen_HK
dc.subject.meshChromosomes, Mammalian - metabolismen_HK
dc.subject.meshDNA Damageen_HK
dc.subject.meshDNA-Binding Proteins - metabolismen_HK
dc.subject.meshDipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry - metabolismen_HK
dc.subject.meshHistones - metabolismen_HK
dc.subject.meshMiceen_HK
dc.subject.meshProteasome Endopeptidase Complex - metabolismen_HK
dc.subject.meshProtein Interaction Mappingen_HK
dc.subject.meshProtein Stabilityen_HK
dc.subject.meshSerine Proteases - chemistry - metabolismen_HK
dc.subject.meshTelomere - chemistryen_HK
dc.subject.meshUbiquitin-Protein Ligases - analysis - chemistry - physiologyen_HK
dc.subject.meshUbiquitinationen_HK
dc.titleThe E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protectionen_HK
dc.typeArticleen_HK
dc.identifier.emailHuen, MSY:huen.michael@hku.hken_HK
dc.identifier.authorityHuen, MSY=rp01336en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/nsmb.2172en_HK
dc.identifier.pmid22101936-
dc.identifier.scopuseid_2-s2.0-82955233817en_HK
dc.identifier.hkuros198265en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-82955233817&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume18en_HK
dc.identifier.issue12en_HK
dc.identifier.spage1400en_HK
dc.identifier.epage1407en_HK
dc.identifier.isiWOS:000298011600029-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridRai, R=8961916400en_HK
dc.identifier.scopusauthoridLi, JM=36698073100en_HK
dc.identifier.scopusauthoridZheng, H=7403441097en_HK
dc.identifier.scopusauthoridLok, GTM=44161157700en_HK
dc.identifier.scopusauthoridDeng, Y=9838946200en_HK
dc.identifier.scopusauthoridHuen, MSY=23004751500en_HK
dc.identifier.scopusauthoridChen, J=35261693300en_HK
dc.identifier.scopusauthoridJin, J=7403588308en_HK
dc.identifier.scopusauthoridChang, S=7405608712en_HK
dc.identifier.citeulike10108065-

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