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Article: A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

TitleA targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability
Authors
Issue Date1998
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 1998, v. 17 n. 24, p. 3115-3124 How to Cite?
AbstractGermline mutations of the Brca1 gene are responsible for most cases of familial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos deficient for Brca1 have been shown to die during early embryogenesis due to a proliferation defect. These findings seem incompatible with the tumor suppress function assigned to this gene and raise questions about the mechanism by which Brca1 mutations cause tumorigenesis. We now directly demonstrate that BRCA1 is responsible for the integrity of the genome. Murine embryos carrying a Brca1 null mutation are developmentally retarded and hypersensitive to γ-irradiation, suggesting a failure in DNA damage repair. This notion is supported by spectral karyotyping (SKY) of metaphase chromosomes, which display numerical and structural aberrations. However, massive chromosomal abnormalities are only observed when a p53(-/-) background is introduced. Thus, a p53 dependent cell cycle checkpoint arrests the mutant embryos and prevents the accumulation of damaged DNA. Brca1(-/-) fibroblasts are not viable, nor are Brca1(-/-):p53(-/-) fibroblasts. However, proliferative foci arise from Brca1(-/-):p53(-/-) cells, probably due to additional mutations that are a consequence of the accumulating DNA damage. We believe that the increased incidence of such additional mutations accounts for the mechanism of tumorigenesis associated with Brca1 mutations in humans.
Persistent Identifierhttp://hdl.handle.net/10722/150741
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorShen, SXen_US
dc.contributor.authorWeaver, Zen_US
dc.contributor.authorXu, Xen_US
dc.contributor.authorLi, Cen_US
dc.contributor.authorWeinstein, Men_US
dc.contributor.authorChen, Len_US
dc.contributor.authorGuan, XYen_US
dc.contributor.authorRied, Ten_US
dc.contributor.authorDeng, CXen_US
dc.date.accessioned2012-06-26T06:09:37Z-
dc.date.available2012-06-26T06:09:37Z-
dc.date.issued1998en_US
dc.identifier.citationOncogene, 1998, v. 17 n. 24, p. 3115-3124en_US
dc.identifier.issn0950-9232en_US
dc.identifier.urihttp://hdl.handle.net/10722/150741-
dc.description.abstractGermline mutations of the Brca1 gene are responsible for most cases of familial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos deficient for Brca1 have been shown to die during early embryogenesis due to a proliferation defect. These findings seem incompatible with the tumor suppress function assigned to this gene and raise questions about the mechanism by which Brca1 mutations cause tumorigenesis. We now directly demonstrate that BRCA1 is responsible for the integrity of the genome. Murine embryos carrying a Brca1 null mutation are developmentally retarded and hypersensitive to γ-irradiation, suggesting a failure in DNA damage repair. This notion is supported by spectral karyotyping (SKY) of metaphase chromosomes, which display numerical and structural aberrations. However, massive chromosomal abnormalities are only observed when a p53(-/-) background is introduced. Thus, a p53 dependent cell cycle checkpoint arrests the mutant embryos and prevents the accumulation of damaged DNA. Brca1(-/-) fibroblasts are not viable, nor are Brca1(-/-):p53(-/-) fibroblasts. However, proliferative foci arise from Brca1(-/-):p53(-/-) cells, probably due to additional mutations that are a consequence of the accumulating DNA damage. We believe that the increased incidence of such additional mutations accounts for the mechanism of tumorigenesis associated with Brca1 mutations in humans.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_US
dc.relation.ispartofOncogeneen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBrca1 Protein - Geneticsen_US
dc.subject.meshCell Divisionen_US
dc.subject.meshChromosome Aberrationsen_US
dc.subject.meshChromosome Disordersen_US
dc.subject.meshGamma Raysen_US
dc.subject.meshGene Targetingen_US
dc.subject.meshGenes, P53en_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Knockouten_US
dc.subject.meshRadiation Tolerance - Geneticsen_US
dc.titleA targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instabilityen_US
dc.typeArticleen_US
dc.identifier.emailGuan, XY:xyguan@hkucc.hku.hken_US
dc.identifier.authorityGuan, XY=rp00454en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid9872327-
dc.identifier.scopuseid_2-s2.0-0032542216en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0032542216&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume17en_US
dc.identifier.issue24en_US
dc.identifier.spage3115en_US
dc.identifier.epage3124en_US
dc.identifier.isiWOS:000077517400005-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridShen, SX=7403431884en_US
dc.identifier.scopusauthoridWeaver, Z=6701479625en_US
dc.identifier.scopusauthoridXu, X=8747937500en_US
dc.identifier.scopusauthoridLi, C=8747937300en_US
dc.identifier.scopusauthoridWeinstein, M=7201569154en_US
dc.identifier.scopusauthoridChen, L=7409440074en_US
dc.identifier.scopusauthoridGuan, XY=7201463221en_US
dc.identifier.scopusauthoridRied, T=7005331565en_US
dc.identifier.scopusauthoridDeng, CX=7202302536en_US

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