Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains.
Germ-line mutations of the BRCA1 gene predispose women to early-onset breast and ovarian cancer by compromising the gene's presumptive function as a tumor suppressor. Although the biochemical properties of BRCA1 polypeptides are not understood, their expression pattern and subcellular localization suggest a role in cell-cycle regulation. When resting cells are induced to proliferate, the steady-state levels of BRCA1 increase in late G1 and reach a maximum during S phase. Moreover, in S phase cells, BRCA1 polypeptides are hyperphosphorylated and accumulate into discrete subnuclear foci termed "BRCA1 nuclear dots." BRCA1 associates in vivo with a structurally related protein termed BARD1. Here we show that the steady-state levels of BARD1, unlike those of BRCA1, remain relatively constant during cell cycle progression. However, immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle, but not during the G1 phase. Nevertheless, BARD1 polypeptides are found exclusively in the nuclear fractions of both G1- and S-phase cells. Therefore, progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1-mediated tumor suppression.
Jin
Y
Y
Department of Microbiology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75235, USA.
Xu
X L
XL
Yang
M C
MC
Wei
F
F
Ayi
T C
TC
Bowcock
A M
AM
Baer
R
R
D019313:BRCA1 Protein / Q000302:isolation & purification*; D001940:Breast / Q000166:cytology; D002352:Carrier Proteins / Q000302:isolation & purification*; D002451:Cell Compartmentation; D002453:Cell Cycle; D002467:Cell Nucleus / Q000648:ultrastructure*; D004847:Epithelial Cells; D005260:Female; D005455:Fluorescent Antibody Technique; D016193:G1 Phase; D006801:Humans; D016196:S Phase; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases
D019313:BRCA1 Protein; D002352:Carrier Proteins; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases