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BRCA1/BARD1 inhibition of mRNA 3' processing involves targeted degradation of RNA polymerase II

Frida E Kleiman1, Foon Wu-Baer, Danae Fonseca

  • 1Department of Biological Sciences, Columbia University, New York, New York 10027, USA.

Genes & Development
|May 21, 2005
PubMed

Insights

The BRCA1/BARD1 complex degrades RNA polymerase II (RNAP II) to inhibit transcription-RNA processing during DNA damage response. This mechanism facilitates DNA repair in mammalian cells.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Mammalian cells have complex DNA damage responses.
  • BRCA1 and BARD1 are tumor suppressors involved in DNA repair.
  • Previous work showed BRCA1/BARD1 inhibits pre-mRNA 3' processing.

Purpose of the Study:

  • To investigate the mechanism by which BRCA1/BARD1 inhibits pre-mRNA 3' processing.
  • To identify the specific component targeted by BRCA1/BARD1.
  • To elucidate the role of RNAP II degradation in DNA damage response.

Main Methods:

  • In vitro assays using purified proteins.
  • siRNA-mediated knockdown of BRCA1 and BARD1.
  • Analysis of nuclear localization and protein accumulation after DNA damage.

Main Results:

  • BRCA1/BARD1 targets RNA polymerase II (RNAP II) for proteasomal degradation.
  • RNAP IIO is a specific in vitro target of BRCA1/BARD1 ubiquitin ligase activity.
  • BRCA1/BARD1 depletion stabilizes RNAP II and reverts processing inhibition after DNA damage.

Conclusions:

  • BRCA1/BARD1 complex initiates degradation of stalled RNAP IIO.
  • This process inhibits coupled transcription-RNA processing.
  • The mechanism facilitates DNA repair following DNA damage.

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