Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.
Germline mutations of the Brca1 tumor suppressor gene predispose women to breast and ovarian cancers. To study mechanisms underlying BRCA1-related tumorigenesis, we derived mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of the Brca1 gene. We show that the mutant cells maintain an intact G1-S cell cycle checkpoint and proliferate poorly. However, a defective G2-M checkpoint in these cells is accompanied by extensive chromosomal abnormalities. Mutant fibroblasts contain multiple, functional centrosomes, which lead to unequal chromosome segregation, abnormal nuclear division, and aneuploidy. These data uncover an essential role of BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G2-M checkpoint and provide a molecular basis for the role of BRCA1 in tumorigenesis.
Xu
X
X
Genetics of Development and Disease Branch, National Institutes of Health, Bethesda, Maryland 20892, USA.
Weaver
Z
Z
Linke
S P
SP
Li
C
C
Gotay
J
J
Wang
X W
XW
Harris
C C
CC
Ried
T
T
Deng
C X
CX
D017398:Alternative Splicing; D000782:Aneuploidy; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D002869:Chromosome Aberrations / Q000235:genetics*; D020090:Chromosome Segregation; D004249:DNA Damage; D005091:Exons / Q000235:genetics*; D005347:Fibroblasts; D016195:G2 Phase / Q000502:physiology*; D019398:Genes, BRCA1; D020287:In Situ Nick-End Labeling; D007621:Karyotyping; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D020033:Protein Isoforms / Q000172:deficiency* / Q000235:genetics; D017384:Sequence Deletion; D008941:Spindle Apparatus / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D019313:BRCA1 Protein; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53