Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability.
The BRCA1 tumor suppressor has been implicated in many cellular pathways, but the mechanisms by which it suppresses tumor formation are not fully understood. In vivo BRCA1 forms a heterodimeric complex with the related BARD1 protein, and its enzymatic activity as a ubiquitin ligase is largely dependent upon its interaction with BARD1. To explore the genetic relationship between BRCA1 and BARD1, we have examined the phenotype of Bard1-null mice. These mice become developmentally retarded and die between embryonic day 7.5 (E7.5) and E8.5. Embryonic lethality results from a severe impairment of cell proliferation that is not accompanied by increased apoptosis. In the absence of p53, the developmental defects associated with Bard1 deficiency are partly ameliorated, and the lethality of Bard1; p53-nullizygous mice is delayed until E9.5. This result, together with the increased chromosomal aneuploidy of Bard1 mutant cells, indicates a role for Bard1 in maintaining genomic stability. The striking similarities between the phenotypes of Bard1-null, Brca1-null, and double Bard1; Brca1-null mice provide strong genetic evidence that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer.
McCarthy
Ellen E
EE
Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Celebi
Julide T
JT
Baer
Richard
R
Ludwig
Thomas
T
D000782:Aneuploidy; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001755:Blastocyst / Q000166:cytology / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002869:Chromosome Aberrations; D019281:Dimerization; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases
D019313:BRCA1 Protein; D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C491163:Bard1 protein, mouse; D044767:Ubiquitin-Protein Ligases