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Article: PALB2 is an integral component of the BRCA complex required for homologous recombination repair

TitlePALB2 is an integral component of the BRCA complex required for homologous recombination repair
Authors
KeywordsBRCA1
BRCA2
FANCN
Issue Date2009
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 17, p. 7155-7160 How to Cite?
AbstractMutations in breast cancer susceptibility gene 1 and 2 {BRCA1 and BRCA2) predispose individuals to breast and ovarian cancer development. We previously reported an in vivo interaction between BRCA1 and BRCA2. However, the biological significance of their association is thus far undefined. Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1,and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. The association between BRCA1 and PALB2 is primarily mediated via apolar bonding between their respective coiled-coil domains. More importantly, BRCA1 mutations identified in cancer patients disrupted the specific interaction between BRCA1 and PALB2. Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations.
Persistent Identifierhttp://hdl.handle.net/10722/90922
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Croucher Foundation
Anna Fuller Fund
National Institutes of Health
Department of Defense
Funding Information:

We thank Prof. David Livingston (Dana-Farber Harvard Cancer Institute, Boston) for providing the pOZC-PALB2 construct and the various antibodies used in this study; Prof. Maria Jasin (Memorial SloanKettering Cancer Center, New York) for the U2OS cells with DR-GFP integration, DR-GFP, and pCBASce plasmids; Prof. Johan P. de Winter (Vrije Universiteit Medical Center, Amsterdam) for EUFA1341 cells; Prof. Richard Baer (Columbia University, NewYork) for the BRCA1 and BARD1 baculoviruses; Drs. Gargi Ghosal, Xiaohua Xu, and Zihua Gong for their assistance in gel filtration chromatography; and Drs. Jingsong Yuan and Jun Huang for insightful discussion. S. M. H. S. is supported by a Postdoctoral fellowship from the Croucher Foundation; M. S. Y. H. by an Anna Fuller Fund fellowship; and J. C. by grants from the National Institutes of Health and an Era of Hope Scholar award from the Department of Defense. J. C. is a member of the Mayo Clinic Breast Specialized Programs of Research Excellence program.

References

 

DC FieldValueLanguage
dc.contributor.authorSy, SMHen_HK
dc.contributor.authorHuen, MSYen_HK
dc.contributor.authorChen, Jen_HK
dc.date.accessioned2010-09-17T10:10:24Z-
dc.date.available2010-09-17T10:10:24Z-
dc.date.issued2009en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2009, v. 106 n. 17, p. 7155-7160en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/90922-
dc.description.abstractMutations in breast cancer susceptibility gene 1 and 2 {BRCA1 and BRCA2) predispose individuals to breast and ovarian cancer development. We previously reported an in vivo interaction between BRCA1 and BRCA2. However, the biological significance of their association is thus far undefined. Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1,and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. The association between BRCA1 and PALB2 is primarily mediated via apolar bonding between their respective coiled-coil domains. More importantly, BRCA1 mutations identified in cancer patients disrupted the specific interaction between BRCA1 and PALB2. Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations.en_HK
dc.languageengen_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subjectBRCA1en_HK
dc.subjectBRCA2en_HK
dc.subjectFANCNen_HK
dc.titlePALB2 is an integral component of the BRCA complex required for homologous recombination repairen_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.doi10.1073/pnas.0811159106en_HK
dc.identifier.pmid19369211en_HK
dc.identifier.pmcidPMC2678481-
dc.identifier.scopuseid_2-s2.0-66349096607en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66349096607&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume106en_HK
dc.identifier.issue17en_HK
dc.identifier.spage7155en_HK
dc.identifier.epage7160en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000265584500052-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSy, SMH=6602984466en_HK
dc.identifier.scopusauthoridHuen, MSY=23004751500en_HK
dc.identifier.scopusauthoridChen, J=7501899830en_HK

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