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A mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin ligase

Andrew A Horwitz1, El Bachir Affar, George F Heine

  • 1Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 11, 2007
PubMed

Insights

The tumor suppressor BRCA1 protein inhibits gene transcription by ubiquitinating key factors, preventing their assembly. This ubiquitin-dependent mechanism reveals BRCA1

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Loss of function in the BRCA1 tumor suppressor protein is a key factor in many breast cancers.
  • BRCA1 was previously known to stimulate transcription, but its role in transcriptional repression was less understood.
  • Few repressed genes and the mechanisms behind BRCA1-mediated repression were not well characterized.

Purpose of the Study:

  • To elucidate the biochemical mechanism by which BRCA1 inhibits gene transcription.
  • To investigate the role of ubiquitination in BRCA1-mediated transcriptional repression.
  • To determine the significance of BRCA1 as a transcriptional repressor in cellular contexts.

Main Methods:

  • In vitro transcription assays were used to identify the mechanism of BRCA1's inhibitory activity.
  • BRCA1's ubiquitination of the transcriptional preinitiation complex was analyzed.
  • RNA interference (RNAi) was employed to knock down endogenous BRCA1 expression and assess repression levels.

Main Results:

  • BRCA1 inhibits transcription through an ubiquitin-dependent mechanism.
  • BRCA1 ubiquitinates the transcriptional preinitiation complex, hindering the stable association of TFIIE and TFIIH.
  • The ubiquitin moiety directly interferes with basal transcription factor assembly, rather than targeting proteins for degradation.
  • BRCA1 functions as a significant transcriptional repressor, comparable to its known activator role.

Conclusions:

  • BRCA1 utilizes an enzymatic activity to ubiquitinate the transcriptional preinitiation complex, thereby repressing transcription.
  • This mechanism involves the ubiquitin moiety directly impeding transcription factor assembly, not protein degradation.
  • BRCA1 plays a dual role in gene regulation, acting as both a transcriptional activator and repressor.

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