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Article: Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8

TitleClass switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8
Authors
Issue Date2010
PublisherRockefeller University Press. The Journal's web site is located at http://www.jem.org
Citation
Journal Of Experimental Medicine, 2010, v. 207 n. 5, p. 973-981 How to Cite?
Abstract53BP1 is a well-known mediator of the cellular response to DNA damage. Two alternative mechanisms have been proposed to explain 53BP1's interaction with DNA double-strand breaks (DSBs), one by binding to methylated histones and the other via an RNF8 E3 ligase-dependent ubiquitylation pathway. The formation of RNF8 and 53BP1 irradiationinduced foci are both dependent on histone H2AX. To evaluate the contribution of the RNF8-dependent pathway to 53BP1 function, we generated RNF8 knockout mice. We report that RNF8 deficiency results in defective class switch recombination (CSR) and accumulation of unresolved immunoglobulin heavy chain-associated DSBs. The CSR DSB repair defect is milder than that observed in the absence of 53BP1 but similar to that found in H2AX-/- mice. Moreover, similar to H2AX but different from 53BP1 deficiency, RNF8-/- males are sterile, and this is associated with defective ubiquitylation of the XY chromatin. Combined loss of H2AX and RNF8 does not cause further impairment in CSR, demonstrating that the two genes function epistatically. Importantly, although 53BP1 foci formation is RNF8 dependent, its binding to chromatin is preserved in the absence of RNF8. This suggests a two-step mechanism for 53BP1 association with chromatin in which constitutive loading is dependent on interactions with methylated histones, whereas DNA damage-inducible RNF8-dependent ubiquitylation allows its accumulation at damaged chromatin.
Persistent Identifierhttp://hdl.handle.net/10722/65449
ISSN
2015 Impact Factor: 11.24
2015 SCImago Journal Rankings: 10.762
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Medical Scientist Training ProgramGM07739
Center for Cancer Research, National Cancer Institute, National Institutes of Health
Funding Information:

I.A. Klein was supported by Medical Scientist Training Program grant GM07739 and is a predoctoral fellow of the Cancer Research Institute. This work was supported by the Intramural Research program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

References

 

DC FieldValueLanguage
dc.contributor.authorSantos, MAen_HK
dc.contributor.authorHuen, MSYen_HK
dc.contributor.authorJankovic, Men_HK
dc.contributor.authorChen, HTen_HK
dc.contributor.authorLópezContreras, AJen_HK
dc.contributor.authorKlein, IAen_HK
dc.contributor.authorWong, Nen_HK
dc.contributor.authorBarbancho, JLRen_HK
dc.contributor.authorFernandezCapetillo, Oen_HK
dc.contributor.authorNussenzweig, MCen_HK
dc.contributor.authorChen, Jen_HK
dc.contributor.authorNussenzweig, Aen_HK
dc.date.accessioned2010-08-06T08:41:33Z-
dc.date.available2010-08-06T08:41:33Z-
dc.date.issued2010en_HK
dc.identifier.citationJournal Of Experimental Medicine, 2010, v. 207 n. 5, p. 973-981en_HK
dc.identifier.issn0022-1007en_HK
dc.identifier.urihttp://hdl.handle.net/10722/65449-
dc.description.abstract53BP1 is a well-known mediator of the cellular response to DNA damage. Two alternative mechanisms have been proposed to explain 53BP1's interaction with DNA double-strand breaks (DSBs), one by binding to methylated histones and the other via an RNF8 E3 ligase-dependent ubiquitylation pathway. The formation of RNF8 and 53BP1 irradiationinduced foci are both dependent on histone H2AX. To evaluate the contribution of the RNF8-dependent pathway to 53BP1 function, we generated RNF8 knockout mice. We report that RNF8 deficiency results in defective class switch recombination (CSR) and accumulation of unresolved immunoglobulin heavy chain-associated DSBs. The CSR DSB repair defect is milder than that observed in the absence of 53BP1 but similar to that found in H2AX-/- mice. Moreover, similar to H2AX but different from 53BP1 deficiency, RNF8-/- males are sterile, and this is associated with defective ubiquitylation of the XY chromatin. Combined loss of H2AX and RNF8 does not cause further impairment in CSR, demonstrating that the two genes function epistatically. Importantly, although 53BP1 foci formation is RNF8 dependent, its binding to chromatin is preserved in the absence of RNF8. This suggests a two-step mechanism for 53BP1 association with chromatin in which constitutive loading is dependent on interactions with methylated histones, whereas DNA damage-inducible RNF8-dependent ubiquitylation allows its accumulation at damaged chromatin.en_HK
dc.languageeng-
dc.publisherRockefeller University Press. The Journal's web site is located at http://www.jem.orgen_HK
dc.relation.ispartofJournal of Experimental Medicineen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe Journal of Experimental Medicine. Copyright © Rockefeller University Press.-
dc.subject.meshImmunoglobulin Class Switching - genetics - physiology-
dc.subject.meshMeiosis - genetics - physiology-
dc.subject.meshUbiquitin-Protein Ligases - deficiency - genetics - physiology-
dc.subject.meshAnimals-
dc.subject.meshChromatin - metabolism-
dc.titleClass switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0022-1007&volume=207&issue=5&spage=973&epage=981&date=2010&atitle=Class+switching+and+meiotic+defects+in+mice+lacking+the+E3+ubiquitin+ligase+RNF8-
dc.identifier.emailHuen, MSY:huen.michael@hku.hken_HK
dc.identifier.authorityHuen, MSY=rp01336en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1084/jem.20092308en_HK
dc.identifier.pmid20385748-
dc.identifier.pmcidPMC2867275-
dc.identifier.scopuseid_2-s2.0-77952294873en_HK
dc.identifier.hkuros170401-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77952294873&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume207en_HK
dc.identifier.issue5en_HK
dc.identifier.spage973en_HK
dc.identifier.epage981en_HK
dc.identifier.isiWOS:000277452100010-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSantos, MA=36132254600en_HK
dc.identifier.scopusauthoridHuen, MSY=23004751500en_HK
dc.identifier.scopusauthoridJankovic, M=7101641030en_HK
dc.identifier.scopusauthoridChen, HT=7501613528en_HK
dc.identifier.scopusauthoridLópezContreras, AJ=36789430000en_HK
dc.identifier.scopusauthoridKlein, IA=35311106800en_HK
dc.identifier.scopusauthoridWong, N=36006580100en_HK
dc.identifier.scopusauthoridBarbancho, JLR=36130997400en_HK
dc.identifier.scopusauthoridFernandezCapetillo, O=6603072926en_HK
dc.identifier.scopusauthoridNussenzweig, MC=7005243263en_HK
dc.identifier.scopusauthoridChen, J=7501899830en_HK
dc.identifier.scopusauthoridNussenzweig, A=7004713866en_HK

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