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BRCA1 directs a selective p53-dependent transcriptional response towards growth arrest and DNA repair targets

Timothy K MacLachlan1, Rishu Takimoto, Wafik S El-Deiry

  • 1Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Molecular and Cellular Biology
|May 25, 2002
PubMed

Insights

BRCA1 (Breast Cancer gene 1) selectively activates the p53 protein to promote DNA repair and cell cycle arrest, rather than apoptosis. This finding clarifies BRCA1

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The tumor suppressive role of BRCA1 (Breast Cancer gene 1) is incompletely understood, though it involves DNA repair and gene transcription.
  • BRCA1 is known to regulate p53-dependent transcription, a critical tumor suppressor protein.
  • BRCA1 overexpression stabilizes wild-type p53 but typically does not induce apoptosis in most cell lines.

Purpose of the Study:

  • To investigate the selectivity of BRCA1 in coactivating p53-dependent target gene activation.
  • To differentiate the transcriptional targets of p53 when stabilized by BRCA1 versus DNA-damaging agents.

Main Methods:

  • Comparative analysis of gene expression profiles induced by BRCA1 stabilization versus DNA damage.
  • Assessment of apoptosis and cell death markers in response to BRCA1 expression and DNA damage.
  • Depletion of BRCA1 in cells expressing wild-type p53 to observe effects on specific gene induction.

Main Results:

  • BRCA1-stabilized p53 preferentially activates transcription of DNA repair and growth arrest genes.
  • p53 stabilized by DNA-damaging agents induces a broader range of genes, including those involved in apoptosis.
  • Depletion of BRCA1 abolished induction of DNA repair genes (e.g., p53R2) but not apoptosis-related genes (e.g., PIG3).
  • BRCA1 conferred diminished p53-dependent cell death in response to adriamycin treatment.

Conclusions:

  • BRCA1 selectively coactivates the p53 transcription factor towards genes mediating DNA repair and cell cycle arrest.
  • BRCA1 does not direct p53 towards apoptosis-inducing genes, explaining the lack of apoptosis upon BRCA1 overexpression.
  • This selective coactivation mechanism contributes to BRCA1's tumor suppressive function by promoting cell cycle arrest over cell death.

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