Abstract
The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase accumulation. High density cDNA array screening of colon, lung, and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control. Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways.
Highlights
The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair
We show here that ectopic expression of BRCA1 using an adenovirus vector (AdBRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity
The BRCA1 protein has been shown to activate transcription when tethered to the GAL4-DNA binding domain (5), inhibit new DNA synthesis when overexpressed (12), and colocalize in nuclear dot structures with Rad51 (16)
Summary
The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways. BRCA1 has been proposed to be tightly linked to the DNA damage response Both BRCA1 and another gene product that segregates with breast cancer, BRCA2, are found in complexes with the human RAD51 protein (16, 17). Brca1-null embryonic stem cells are defective in their ability to repair thymine glycols after H2O2 treatment (19) This oxidative DNA damage is most quickly alleviated by transcriptioncoupled repair mechanisms that appear to involve BRCA1. A targeted deletion of Brca exon 11 results in genetic instability, hypothesized to be due to unrepaired DNA damage (20)
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